US20120094975A1 - Pyrido [5, 4-d] pyrimidines as cell proliferation inhibitors - Google Patents
Pyrido [5, 4-d] pyrimidines as cell proliferation inhibitors Download PDFInfo
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- US20120094975A1 US20120094975A1 US13/062,058 US200913062058A US2012094975A1 US 20120094975 A1 US20120094975 A1 US 20120094975A1 US 200913062058 A US200913062058 A US 200913062058A US 2012094975 A1 US2012094975 A1 US 2012094975A1
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- iii
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- SJRUYJFRHDYWHH-UHFFFAOYSA-N COCCN1CCN(C2=NC3=C(NC4=CC(C(=O)NC5=NOC(C(C)(C)C)=C5)=CC=C4F)N=CN=C3C=N2)CC1 Chemical compound COCCN1CCN(C2=NC3=C(NC4=CC(C(=O)NC5=NOC(C(C)(C)C)=C5)=CC=C4F)N=CN=C3C=N2)CC1 SJRUYJFRHDYWHH-UHFFFAOYSA-N 0.000 description 1
- HJMKLDBFLNKCHZ-UHFFFAOYSA-M COCCN1CCN(C2=NC3=C(NC4=CC(C(=O)O)=CC=C4C)N=CN=C3C=N2)CC1.COCCN1CCN(C2=NC3=C(NC4=CC(C(=O)OC)=CC=C4C)N=CN=C3C=N2)CC1.[Li]O Chemical compound COCCN1CCN(C2=NC3=C(NC4=CC(C(=O)O)=CC=C4C)N=CN=C3C=N2)CC1.COCCN1CCN(C2=NC3=C(NC4=CC(C(=O)OC)=CC=C4C)N=CN=C3C=N2)CC1.[Li]O HJMKLDBFLNKCHZ-UHFFFAOYSA-M 0.000 description 1
- HOGXRCJKMHZPEZ-UHFFFAOYSA-N COCCNC1=NC2=C(NC3=CC(C(=O)NC4=CC(C(F)(F)F)=C(N(C)CCN(C)C)C=C4)=CC=C3C)N=CN=C2C=N1 Chemical compound COCCNC1=NC2=C(NC3=CC(C(=O)NC4=CC(C(F)(F)F)=C(N(C)CCN(C)C)C=C4)=CC=C3C)N=CN=C2C=N1 HOGXRCJKMHZPEZ-UHFFFAOYSA-N 0.000 description 1
- DELWEBOBTTWIEA-UHFFFAOYSA-N COCCNC1=NC2=C(NC3=CC(C(=O)NC4=CC(C(F)(F)F)=CC(OCCN(C)C)=C4)=CC=C3C)N=CN=C2C=N1 Chemical compound COCCNC1=NC2=C(NC3=CC(C(=O)NC4=CC(C(F)(F)F)=CC(OCCN(C)C)=C4)=CC=C3C)N=CN=C2C=N1 DELWEBOBTTWIEA-UHFFFAOYSA-N 0.000 description 1
- ZJQJDTXINMLVBG-UHFFFAOYSA-N COCCNC1=NC2=C(NC3=CC(C(=O)NC4=NOC(C(C)(C)C)=C4)=CC=C3C)N=CN=C2C=N1 Chemical compound COCCNC1=NC2=C(NC3=CC(C(=O)NC4=NOC(C(C)(C)C)=C4)=CC=C3C)N=CN=C2C=N1 ZJQJDTXINMLVBG-UHFFFAOYSA-N 0.000 description 1
- ZQTOISNPGGZJLD-IBGZPJMESA-N COC[C@@H]1CCCN1C1=NC2=C(NC3=CC(C(=O)NC4=CC(C(F)(F)F)=C(OC)C=C4)=CC=C3C)N=CN=C2C=N1 Chemical compound COC[C@@H]1CCCN1C1=NC2=C(NC3=CC(C(=O)NC4=CC(C(F)(F)F)=C(OC)C=C4)=CC=C3C)N=CN=C2C=N1 ZQTOISNPGGZJLD-IBGZPJMESA-N 0.000 description 1
- YHPWXTCRZZWCGO-SFHVURJKSA-N COC[C@@H]1CCCN1C1=NC2=C(NC3=CC(C(=O)NC4=NOC(C(C)(C)C)=C4)=CC=C3C)N=CN=C2C=N1 Chemical compound COC[C@@H]1CCCN1C1=NC2=C(NC3=CC(C(=O)NC4=NOC(C(C)(C)C)=C4)=CC=C3C)N=CN=C2C=N1 YHPWXTCRZZWCGO-SFHVURJKSA-N 0.000 description 1
- GMPDBWLUWPBXNJ-UHFFFAOYSA-N CSC1=NC2=C(Cl)N=CN=C2C=N1.CSC1=NC2=C(O)N=CN=C2C=N1.O=S(Cl)Cl Chemical compound CSC1=NC2=C(Cl)N=CN=C2C=N1.CSC1=NC2=C(O)N=CN=C2C=N1.O=S(Cl)Cl GMPDBWLUWPBXNJ-UHFFFAOYSA-N 0.000 description 1
- ICFWMKHWGKSYOP-UHFFFAOYSA-N Cc(c(N)c1)ccc1C(Nc(cc1)cc(C(F)(F)F)c1OC)=O Chemical compound Cc(c(N)c1)ccc1C(Nc(cc1)cc(C(F)(F)F)c1OC)=O ICFWMKHWGKSYOP-UHFFFAOYSA-N 0.000 description 1
- PUSROPBJVVEIDC-UHFFFAOYSA-N Cc(c(Nc1ncnc(c(N)n2)c1nc2Cl)c1)ccc1C(Nc(cc1)cc(C(F)(F)F)c1OC)=O Chemical compound Cc(c(Nc1ncnc(c(N)n2)c1nc2Cl)c1)ccc1C(Nc(cc1)cc(C(F)(F)F)c1OC)=O PUSROPBJVVEIDC-UHFFFAOYSA-N 0.000 description 1
- YJVUWNWSQQHMSM-UHFFFAOYSA-N Cc(c(Nc1ncnc2c1nc(N1CCN(CCOC)CC1)nc2)c1)ccc1C(O)=O Chemical compound Cc(c(Nc1ncnc2c1nc(N1CCN(CCOC)CC1)nc2)c1)ccc1C(O)=O YJVUWNWSQQHMSM-UHFFFAOYSA-N 0.000 description 1
- ZQNROBXRNRRCCI-UHFFFAOYSA-N Cc(c(Nc1ncnc2c1nc(N1CCN(CCOC)CC1)nc2)c1)ccc1C(OC)=O Chemical compound Cc(c(Nc1ncnc2c1nc(N1CCN(CCOC)CC1)nc2)c1)ccc1C(OC)=O ZQNROBXRNRRCCI-UHFFFAOYSA-N 0.000 description 1
- ZYKZEGDYBZOIIO-UHFFFAOYSA-N Cc(ccc(NC(c1cccc(C(F)(F)F)c1)=O)c1)c1Nc1ncnc2c1nc(N(CCC1)CCN1C1CC1)nc2N Chemical compound Cc(ccc(NC(c1cccc(C(F)(F)F)c1)=O)c1)c1Nc1ncnc2c1nc(N(CCC1)CCN1C1CC1)nc2N ZYKZEGDYBZOIIO-UHFFFAOYSA-N 0.000 description 1
- GQQNQNNSHIRTQI-UHFFFAOYSA-N Cc(ccc(NC(c1cccc(C(F)(F)F)c1)=O)c1)c1Nc1ncnc2c1nc(N1C(C3)CN(C)C3C1)nc2N Chemical compound Cc(ccc(NC(c1cccc(C(F)(F)F)c1)=O)c1)c1Nc1ncnc2c1nc(N1C(C3)CN(C)C3C1)nc2N GQQNQNNSHIRTQI-UHFFFAOYSA-N 0.000 description 1
- VCAWHMSXJOKAIX-UHFFFAOYSA-N Cc(ccc(NC(c1cccc(C(F)(F)F)c1)=O)c1)c1Nc1ncnc2c1nc(NCc1ccncc1)nc2N Chemical compound Cc(ccc(NC(c1cccc(C(F)(F)F)c1)=O)c1)c1Nc1ncnc2c1nc(NCc1ccncc1)nc2N VCAWHMSXJOKAIX-UHFFFAOYSA-N 0.000 description 1
- UFPULLZJLIUPNM-UHFFFAOYSA-N ClC1=NC2=C(Cl)N=CN=C2C(Cl)=N1.NC1=NC(Cl)=NC2=C(Cl)N=CN=C12 Chemical compound ClC1=NC2=C(Cl)N=CN=C2C(Cl)=N1.NC1=NC(Cl)=NC2=C(Cl)N=CN=C12 UFPULLZJLIUPNM-UHFFFAOYSA-N 0.000 description 1
- GXVOUMUGJUGJEI-UHFFFAOYSA-N ClC1=NC2=C(Cl)N=CN=C2C(Cl)=N1.OC1=NC2=C(O)N=CN=C2C(O)=N1 Chemical compound ClC1=NC2=C(Cl)N=CN=C2C(Cl)=N1.OC1=NC2=C(O)N=CN=C2C(O)=N1 GXVOUMUGJUGJEI-UHFFFAOYSA-N 0.000 description 1
- GRKDOTNJVRGFRV-UHFFFAOYSA-N ClC1=NC=NC2=C(Cl)N=CN=C12.OC1=NC=NC2=C(O)N=CN=C12 Chemical compound ClC1=NC=NC2=C(Cl)N=CN=C12.OC1=NC=NC2=C(O)N=CN=C12 GRKDOTNJVRGFRV-UHFFFAOYSA-N 0.000 description 1
- DQJRFVLACBXETO-UHFFFAOYSA-N Clc1ncnc2c1ncnc2Cl Chemical compound Clc1ncnc2c1ncnc2Cl DQJRFVLACBXETO-UHFFFAOYSA-N 0.000 description 1
- OHMGELDVCHKSLN-UHFFFAOYSA-N NC1=CC(C(=O)NC2=CC(C(F)(F)F)=CC=C2)=CC=C1Cl.NC1=NC(Cl)=NC2=C(Cl)N=CN=C12.NC1=NC(Cl)=NC2=C(NC3=CC(C(=O)NC4=CC(C(F)(F)F)=CC=C4)=CC=C3Cl)N=CN=C12 Chemical compound NC1=CC(C(=O)NC2=CC(C(F)(F)F)=CC=C2)=CC=C1Cl.NC1=NC(Cl)=NC2=C(Cl)N=CN=C12.NC1=NC(Cl)=NC2=C(NC3=CC(C(=O)NC4=CC(C(F)(F)F)=CC=C4)=CC=C3Cl)N=CN=C12 OHMGELDVCHKSLN-UHFFFAOYSA-N 0.000 description 1
- XCWLQGPXDAJMAJ-UHFFFAOYSA-N Nc1nc(Cl)nc2c1ncnc2Cl Chemical compound Nc1nc(Cl)nc2c1ncnc2Cl XCWLQGPXDAJMAJ-UHFFFAOYSA-N 0.000 description 1
- DBHUIOMOLAVFAS-UHFFFAOYSA-N O=C(NC1=CC(C(F)(F)F)=CC=N1)C1=CC=C(F)C(NC2=C3N=C(N4CCOCC4)N=CC3=NC=N2)=C1 Chemical compound O=C(NC1=CC(C(F)(F)F)=CC=N1)C1=CC=C(F)C(NC2=C3N=C(N4CCOCC4)N=CC3=NC=N2)=C1 DBHUIOMOLAVFAS-UHFFFAOYSA-N 0.000 description 1
- GDAJGNABZPYVMZ-UHFFFAOYSA-N O=C(NC1CCOC1)C1=CC=C(F)C(NC2=C3N=C(NC4CCOC4)N=CC3=NC=N2)=C1 Chemical compound O=C(NC1CCOC1)C1=CC=C(F)C(NC2=C3N=C(NC4CCOC4)N=CC3=NC=N2)=C1 GDAJGNABZPYVMZ-UHFFFAOYSA-N 0.000 description 1
- QAGDGAGJUTYJRT-UHFFFAOYSA-N Oc1ncnc2c1ncnc2O Chemical compound Oc1ncnc2c1ncnc2O QAGDGAGJUTYJRT-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Definitions
- the present invention relates to new compounds of general formula (1)
- the aim of the present invention is to discover new active substances which can be used for the prevention and/or treatment of diseases characterised by excessive or abnormal cell proliferation.
- compounds of general formula (1) wherein the groups R 1 to R 4 , X 1 , X 2 , X 3 , L 1 and L 2 have the meanings given hereinafter act as inhibitors of specific signal enzymes which are involved in controlling cell proliferation.
- the compounds according to the invention may be used for example for the treatment of diseases connected with the activity of these signal enzymes and characterised by excessive or abnormal cell proliferation.
- the present invention therefore relates to compounds of general formula (1)
- R 1 denotes hydrogen or a group optionally substituted by one or more identical or different R b and/or R c , selected from among C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl, or a suitable substituent, selected from among —OR c , —SR c , —NR c R c , —NR c NR c R c and —S(O)R c ;
- R 2 denotes a group optionally substituted by one or more identical or different R b and/or R c , selected from among C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl;
- R 3 is selected from among hydrogen, C 1-4 alkyl
- R 3 denotes hydrogen
- R 3 denotes —NH 2 or —NHMe.
- R 1 denotes hydrogen
- the invention in another aspect (A1B1) the invention relates to compounds (1), wherein R 1 and R 3 denote hydrogen.
- R 1 is a group optionally substituted by one or more identical or different R b and/or R 1 , selected from among 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl, and R b and R c are as hereinbefore defined.
- R 1 is a 3-7 membered, monocyclic and nitrogen-containing heterocycloalkyl or 6-10 membered, bicyclic and nitrogen-containing heterocycloalkyl optionally substituted by one or more identical or different R b and/or R c ,
- R 1 is bound to the pyrimido[5,4-d]pyrimidine structure through a nitrogen atom, and R b and R c are as hereinbefore defined.
- R 1 is a group optionally substituted by one or more identical or different R b and/or R c , selected from among piperidyl, perhydro-1,4-diazepinyl, piperazinyl, octahydro-pyrrolo[1,2-c]pyrazinyl, 2,5-diazabicyclo[2,2,1]heptyl, octahydro-pyrido[1,2-c]pyrazinyl, perhydro-1,4-oxazepinyl, morpholinyl, pyrrolidinyl, perhydroazepinyl, thiomorpholinyl, thiazolidinyl and azetidinyl, R 1 is bound to the pyrimido[5,4-d]pyrimidine structure via a nitrogen atom, and R b and R c are as hereinbefore defined.
- R 1 is a 2-methyl-2,7-diazaspiro[4.4]nonyl optionally substituted by one or more identical or different R b and/or R c , which binds to the pyrimido[5,4-d]pyrimidine structure via a nitrogen atom, and R b and R c are as hereinbefore defined.
- the invention relates to compounds (1) with one of the structural aspects B2 to B5,
- R 1 is heterocycloalkyl which is bound to the pyrimido[5,4-d]pyrimidine structure via a nitrogen atom and is optionally substituted by one or more substituents, each independently selected from among R b1 and R c1 ;
- R 1 is selected from among
- R 1 denotes —NR c2 R c3 and R c2 and R c3 are each defined as R c defined hereinbefore.
- R 1 denotes —NR c2 R c3 and R c2 is selected from among hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl
- R c3 is a group optionally substituted by one or more identical or different R d3 and/or R e3 , selected from among C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl and 3-14 membered heterocycloalkyl
- each R d3 is selected independently of one another from among halogen, —NR e3 R e3 and —OR e3
- each R e3 independently of one another denotes hydrogen or a group optionally substituted by one or more identical or different R f3 and/or R g3 , selected from among C 1-6 alkyl, C 6-10 aryl, 5-12 membered heteroaryl and 3-14 membered hetero
- the invention relates to compounds (1) with one of the structural aspects B8 or B9, wherein
- R c2 denotes hydrogen
- R 1 is selected from among
- the invention relates to compounds (1) with one of the structural aspects B8 or B9, wherein
- R c2 denotes methyl or ethyl.
- R 1 is selected from among
- R 4 denotes fluorine, bromine, chlorine or methyl.
- X 1 denotes CR 4*-1
- X 2 denotes CR 4*-2
- X 3 denotes CR 4*-3 and
- X 1 , X 2 and X 3 each denote CH.
- X 1 denotes nitrogen
- X 2 denotes CR 4*-2
- X 3 denotes CR 4*-3 and R 4*-2 and R 4*-3 are each selected from among hydrogen, fluorine, bromine, chlorine and methyl and at least one of the groups R 4*-2 and R 4*-3 denotes hydrogen.
- X 1 denotes nitrogen
- X 2 denotes CH
- X 3 denotes CH.
- L 1 denotes —NH— or —NMe-.
- R 2 is a group optionally substituted by one or more identical or different R b and/or R c , selected from among C 6-10 aryl and 5-12 membered heteroaryl, and R b and R c are as hereinbefore defined.
- R 2 is a group optionally substituted by one or more identical or different R b and/or R c , selected from among phenyl and 5-6 membered heteroaryl, and R b and R c are as hereinbefore defined.
- R 2 is a 5-6 membered heteroaryl optionally substituted by one or more identical or different R b and/or R c and R b and R c are as hereinbefore defined.
- R 2 is a heteroaryl which is selected from among furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, triazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl and pyrimidyl, and is optionally substituted by one or two substituents, each independently selected from among C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, 1-methylbutyl, 1-ethylpropyl, isopentyl, neopentyl, trifluoromethyl, difluoromethyl,
- R 2 is a phenyl optionally substituted by one or more identical or different R b and/or R c , and R b and R c are as hereinbefore defined.
- R 2 denotes a phenyl
- At least one of the groups R 5 to R 8 is not hydrogen.
- R 5 is selected from among
- R 2 is selected from among
- R′ denotes the binding site to the linker unit L 2 .
- R 2 is selected from among
- R′ denotes the binding site to the linker unit L 2 .
- R 2 is selected from among
- R′ denotes the binding site to the linker unit L 2 .
- L 2 denotes (R 2 )—NHC(O)—.
- L 2 denotes (R 2 )—C(O)NH—.
- All the above-mentioned structural aspects A to G relating to different molecular parts of the compounds (1) according to the invention may be permutated with one another as desired to form combinations ABCDEFG, so as to obtain preferred compounds (1).
- Each combination ABCDEFG represents and defines individual embodiments or generic partial amounts of compounds according to the invention. Every individual embodiment or partial amount defined by this combination is expressly included and is an object of the invention.
- the invention relates to compounds—or the pharmacologically acceptable salts thereof—of general formula (1) as medicaments.
- the invention relates to pharmaceutical preparations, containing as active substance one or more compounds of general formula (1) or the pharmacologically acceptable salts thereof, optionally in combination with conventional excipients and/or carriers.
- the invention relates to compounds of general formula (1) for use in the treatment and/or prevention of cancer, infections, inflammations and autoimmune diseases.
- the invention relates to compounds of general formula (1) for use in the treatment and/or prevention of cancer.
- the invention in another aspect relates to a pharmaceutical preparation comprising a compound of general formula (1), while the compounds (1) may optionally also be in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof or as the respective pharmacologically acceptable salts of all the above-mentioned forms, and at least one other cytostatic or cytotoxic active substance different from formula (1).
- heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl refers to the total atomic number of all the ring members or chain members or the total of all the ring and chain members.
- Alkyl is made up of the sub-groups saturated hydrocarbon chains and unsaturated hydrocarbon chains, while the latter may be further subdivided into hydrocarbon chains with a double bond (alkenyl) and hydrocarbon chains with a triple bond (alkynyl).
- Alkenyl contains at least one double bond, alkynyl at least one triple bond. If a hydrocarbon chain should have both at least one double bond and at least one triple bond, by definition it belongs to the alkynyl sub-group. All the above-mentioned sub-groups may be further subdivided into straight-chain (unbranched) and branched. If an alkyl is substituted, it may be mono- or polysubstituted independently of one another at all the hydrogen-carrying carbon atoms. Examples of individual sub-groups are listed below:
- butadienyl pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl etc. unless otherwise stated are meant unsaturated hydrocarbon groups with the corresponding number of carbon atoms and two double bonds, including all the isomeric forms, also (Z)/(E)-isomers, where applicable.
- propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl etc. unless otherwise stated are meant unsaturated hydrocarbon groups with the corresponding number of carbon atoms and a triple bond, including all the isomeric forms.
- alkylene can also be derived.
- Alkylene unlike alkyl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from an alkyl.
- Corresponding groups are for example —CH 3 and —CH 2 , —CH 2 CH 3 and —CH 2 CH 2 or >CHCH 3 etc. For all the subgroups of alkyl there are correspondences for alkylene.
- heteroatoms oxygen, nitrogen and sulphur atoms.
- heteroalkyl groups which are derived from the alkyl as hereinbefore defined in its widest sense by replacing, in the hydrocarbon chains, one or more of the groups —CH 3 independently of one another by the groups —OH, —SH or —NH 2 , one or more of the groups —CH 2 — independently of one another by the groups —O—, —S— or —NH—, one or more of the groups >CH— by the group >N—, one or more of the groups ⁇ CH— by the group ⁇ N—, one or more of the groups ⁇ CH 2 by the group ⁇ NH or one or more of the groups ⁇ CH by the group ⁇ N, while a total of not more than three heteroatoms may be present in one heteroalkyl, there must be at least one carbon atom between two oxygen atoms and between two sulphur atoms or between one oxygen and one sulphur atom and the group as a whole must have chemical stability.
- heteroalkyl is made up of the sub-groups saturated hydrocarbon chains with heteroatom(s), heteroalkenyl and heteroalkynyl, and it may be further subdivided into straight-chain (unbranched) and branched. If a heteroalkyl is substituted, it may be mono- or polysubstituted independently of one another at all the hydrogen-carrying oxygen, sulphur, nitrogen and/or carbon atoms. Heteroalkyl itself as a substituent may be attached to the molecule both through a carbon atom and through a heteroatom. The following are listed by way of example:
- heteroalkylene can also be derived.
- Heteroalkylene unlike heteroalkyl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from a heteroalkyl.
- Corresponding groups are for example —CH 2 NH 2 and —CH 2 NH— or >CHNH 2 , —NHCH 3 and >NCH 3 or —NHCH 2 —, —CH 2 OCH 3 and —CH 2 OCH 2 — or >CHOCH 3 etc.
- Haloalkyl is derived from alkyl as hereinbefore defined in its broadest sense, by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different.
- a direct result of the indirect definition/derivation from alkyl is that haloalkyl is made up of the sub-groups saturated hydrohalogen chains, haloalkenyl and haloalkynyl, and it may be further subdivided into straight-chain (unbranched) and branched. If a haloalkyl is substituted, it may be mono- or polysubstituted independently of one another at all the hydrogen-carrying carbon atoms. Typical examples are listed below:
- haloalkylene can also be derived.
- Haloalkylene unlike haloalkyl is bivalent and requires two bonding partners.
- the second valency is produced by removing a hydrogen atom from a haloalkyl.
- Corresponding groups are for example —CH 2 F and —CHF—, —CHFCH 2 F and —CHFCHF— or >CFCH 2 F etc.
- Halogen encompasses fluorine, chlorine, bromine and/or iodine atoms.
- Cycloalkyl is made up of the sub-groups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spirohydrocarbon rings, while each sub-group may be further subdivided into saturated and unsaturated (cycloalkenyl).
- unsaturated is meant that there is at least one double bond in the ring system, but no aromatic system is formed.
- bicyclic hydrocarbon rings two rings are linked such that they share at least two carbon atoms.
- spirohydrocarbon rings one carbon atom (spiroatom) is shared by two rings.
- Cycloalkyl itself as a substituent may be attached to the molecule through any suitable position of the ring system. The following individual sub-groups are listed by way of example:
- cycloalkylene can also be derived.
- Cycloalkylene unlike cycloalkyl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from a cycloalkyl.
- Corresponding groups are for example cyclohexyl and
- Cycloalkylalkyl refers to the combination of the alkyl in question, as hereinbefore defined, with cycloalkyl, both in their widest sense.
- cycloalkylalkyl may also be regarded as a combination of cycloalkyl with alkylene.
- cycloalkylalkyl is obtained by first linking an alkyl as substituent directly with the molecule and then substituting with a cycloalkyl.
- the linking of alkyl and cycloalkyl may be carried out in both groups using carbon atoms that are suitable for this purpose.
- the respective subgroups of alkyl (alkylene) and cycloalkyl are also included in the combination of the two groups.
- Aryl denotes mono-, bi- or tricyclic carbon rings with at least one aromatic ring. If an aryl is substituted, the substitution may be mono- or polysubstitution in each case, at all the hydrogen-carrying carbon atoms, independently of one another.
- Aryl itself may be linked to the molecule as substituent via any suitable position of the ring system. Typical examples are listed below:
- arylene can also be derived.
- Arylene unlike aryl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from an aryl.
- Corresponding groups are for example phenyl and
- Arylalkyl denotes the combination of the groups alkyl and aryl as hereinbefore defined, in each case in their broadest sense.
- arylalkyl may also be regarded as a combination of aryl with alkylene.
- arylalkyl is obtained by first linking an alkyl as substituent directly to the molecule and substituting it with an aryl group.
- the alkyl and aryl may be linked in both groups via any carbon atoms suitable for this purpose.
- the respective sub-groups of alkyl (alkylene) and aryl are also included in the combination of the two groups. Typical examples are listed below:
- Heteroaryl denotes monocyclic aromatic rings or polycyclic rings with at least one aromatic ring, which, compared with corresponding aryl or cycloalkyl, contain instead of one or more carbon atoms one or more identical or different heteroatoms, selected independently of one another from among nitrogen, sulphur and oxygen, while the resulting group must be chemically stable.
- the prerequisite for the presence of heteroaryl is a heteroatom and an aromatic system, although it need not necessarily be a heteroaromatic system.
- heteroaryl may according to the definition be a heteroaryl.
- heteroaryl is substituted, the substitution may be mono- or polysubstitution in each case, at all the hydrogen-carrying carbon and/or nitrogen atoms, independently of one another. Heteroaryl itself as substituent may be linked to the molecule via any suitable position of the ring system, both carbon and nitrogen. Typical examples are listed below.
- heteroarylene can also be derived.
- Heteroarylene unlike heteroaryl is bivalent and requires two bonding partners.
- Formally the second valency is produced by removing a hydrogen atom from a heteroaryl.
- Heteroarylalkyl denotes the combination of the alkyl in question as hereinbefore defined with heteroaryl, both in their broadest sense.
- heteroarylalkyl may also be regarded as a combination of heteroaryl with alkylene.
- Formally heteroarylalkyl is obtained by first linking an alkyl as substituent directly with the molecule and then substituting it with a heteroaryl. The linking of the alkyl and heteroaryl may be achieved on the alkyl side via any carbon atoms suitable for this purpose and on the heteroaryl side via any carbon or nitrogen atoms suitable for this purpose.
- the respective sub-groups of alkyl (alkylene) and heteroaryl are also included in the combination of the two groups.
- heterocycloalkyl groups which are derived from the cycloalkyl as hereinbefore defined if in the hydrocarbon rings one or more of the groups —CH 2 — are replaced independently of one another by the groups —O—, —S— or —NH— or one or more of the groups ⁇ CH— are replaced by the group ⁇ N—, while not more than five heteroatoms may be present in total, there must be at least one carbon atom between two oxygen atoms and between two sulphur atoms or between one oxygen and one sulphur atom and the group as a whole must be chemically stable.
- Heteroatoms may simultaneously be present in all the possible oxidation stages (sulphur ⁇ sulphoxide —SO—, sulphone —SO 2 —; nitrogen ⁇ N-oxide). It is immediately apparent from the indirect definition/derivation from cycloalkyl that heterocycloalkyl is made up of the sub-groups monocyclic hetero-rings, bicyclic hetero-rings and spirohetero-rings, while each sub-group can also be further subdivided into saturated and unsaturated (heterocycloalkenyl).
- unsaturated means that in the ring system in question there is at least one double bond, but no aromatic system is formed.
- bicyclic hetero-rings two rings are linked such that they have at least two atoms in common.
- one carbon atom spiroatom
- the substitution may be mono- or polysubstitution in each case, at all the hydrogen-carrying carbon and/or nitrogen atoms, independently of one another.
- Heterocycloalkyl itself as substituent may be linked to the molecule via any suitable position of the ring system. Typical examples of individual sub-groups are listed below.
- heterocycloalkylene can also be derived.
- Heterocycloalkylene unlike heterocycloalkyl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from a heterocycloalkyl.
- Corresponding groups are for example piperidinyl and
- Heterocycloalkylalkyl denotes the combination of the alkyl in question as hereinbefore defined with heterocycloalkyl, both in their broadest sense.
- heterocycloalkylalkyl may also be regarded as a combination of heterocycloalkyl with alkylene.
- Formally heterocycloalkyl is obtained by first linking an alkyl as substituent directly with the molecule and then substituting it with a heterocycloalkyl. The linking of the alkyl and heterocycloalkyl may be achieved on the alkyl side via any carbon atoms suitable for this purpose and on the heterocycloalkyl side via any carbon or nitrogen atoms suitable for this purpose.
- the respective sub-groups of alkyl and heterocycloalkyl are also included in the combination of the two groups.
- substituted By is substituted is meant that a hydrogen atom that is bound directly to the atom under consideration is replaced by another atom or another group of atoms (substituent). Depending on the starting conditions (number of hydrogen atoms) mono- or polysubstitution may take place at an atom.
- Bivalent substituents such as for example ⁇ S, ⁇ NR, ⁇ NOR, ⁇ NNRR, ⁇ NN(R)C(O)NRR, ⁇ N 2 or the like may only be substituents at carbon atoms, while the bivalent substituent ⁇ O may also be a substituent of sulphur.
- substitution by a bivalent substituent may only take place at ring systems and requires exchange for two geminal hydrogen atoms, i.e. hydrogen atoms that are bound to the same carbon atom saturated before the substitution. Substitution by a bivalent substituent is therefore only possible at the group —CH 2 — or sulphur atoms of a ring system.
- suitable substituent denotes a substituent which on the one hand is suitable on account of its valency and on the other hand leads to a system with chemical stability.
- the dotted line indicates that the ring system may be attached to the molecule via the carbon 1 or 2, i.e. is equivalent to the following diagram
- Groups or substituents are frequently selected from among alternative groups/substituents with a corresponding group designation (e.g. R a , R b etc). If a group of this kind is used repeatedly to define a compound according to the invention in different parts of the molecule, it should always be borne in mind that the respective uses are to be regarded as being totally independent of one another.
- Microwave reactions are carried out in an initiator/reactor made by Biotage or in an Explorer made by CEM in sealed containers (preferably 2, 5 or 20 mL), preferably with stirring.
- MLC medium pressure chromatography
- silica gel made by Millipore (name: Granula Silica Si-60A 35-70 ⁇ m) or C-18 RP-silica gel (RP-phase) made by Macherey Nagel (name: Polygoprep 100-50 C18) is used.
- Automated normal phase chromatography is also carried out on a CombiFlash Companion XL apparatus in combination with a CombiFlash Foxy 200 fraction collector made by Isco.
- RediSepRf 120 g silica gel
- one-way columns are used.
- the thin layer chromatography is carried out on ready-made silica gel 60 TLC plates on glass (with fluorescence indicator F-254) made by Merck.
- the preparative high pressure chromatography (HPLC) of the example compounds according to the invention is carried out with columns made by Waters (names: XTerra Prep. MS C18, 5 ⁇ m, 30 ⁇ 100 mm or XTerra Prep. MS C18, 5 ⁇ m, 50 ⁇ 100 mm OBD or Symmetrie C18, 5 ⁇ m, 19 ⁇ 100 mm or Sunfire C18 OBD, 19 ⁇ 100 mm, 5 ⁇ m or Sunfire Prep C 10 ⁇ m OBD 50 ⁇ 150 mm or X-Bridge Prep C18 5 ⁇ m OBD 19 ⁇ 50 mm), Agilent (name: Zorbax SB-C8 5 ⁇ m PrepHT 21.2 ⁇ 50 mm) and Phenomenex (names: Gemini C18 5 ⁇ m AXIA 21.2 ⁇ 50 mm or Gemini C18 10 ⁇ m 50 ⁇ 150 mm). Different gradients of H 2 O/acetonitrile or H 2 O/MeOH are used to elute the compounds,
- HPLC high pressure chromatography
- the analytical HPLC (reaction control) of intermediate compounds is carried out using columns made by Agilent (names: Zorbax SB-C8, 5 ⁇ m, 21.2 ⁇ 50 mm or Zorbax SB-C8 3.5 ⁇ m 2.1 ⁇ 50 mm) and Phenomenex (name: Gemini C18 3 ⁇ m 2 ⁇ 30 mm).
- the analytical equipment is also equipped with a mass detector in each case.
- the compounds according to the invention are prepared by the methods of synthesis described hereinafter, in which the substituents of the general formulae have the meanings given hereinbefore. These methods are intended as an illustration of the invention, without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or may be prepared analogously to known compounds or methods described herein. Substances described in the literature are prepared according to the published methods of synthesis.
- Trisubstituted pyrimidopyrimidines I may be obtained for example by two alternative methods according to Reaction scheme A (synthesis route 1 or 2).
- A-1 the complete left-hand molecular part of the end compounds I is thereby introduced into the intermediate compound Z-2, so that finally there only remains the substitution in the 2-position by components R 1 —H (E-3), which are preferably primary and secondary (also cyclic) amines and alcohols (in the form of the alkoxides).
- the components A-1 are obtained by amide coupling of the nitrocarboxylic acids E-1 with amines E-2 to form the intermediate product Z-1 and subsequent reduction of the nitro group.
- common coupling reagents as used in peptide chemistry e.g. HATU or TBTU
- the nitro acids E-1 are activated in some other way, e.g. as acid halides (e.g. with thionyl chloride, oxalyl chloride, GHOSEZ reagent).
- P-1a Alternatively to P-1a other educts P-1 are possible which allow successive and selective substitution, i.e. have other leaving groups.
- Both the group R 1 and the group R 2 of compounds I according to the invention may be modified in other reaction steps (not shown), to obtain other compounds I according to the invention. These reaction steps may be reactions of substitution, alkylation, acylation or addition.
- E-1a (2.0 g, 11.04 mmol) is taken up in DCM (40 mL) and mixed with TEA (5.1 mL, 27.6 mmol) and HATU (6.3 g, 16.6 mmol).
- aniline E-2b (3.41 g, 11.04 mmol) is added and the mixture is stirred for another 2 h at RT.
- For working up it is diluted with water and the phases are separated. The organic phase is extracted 1 ⁇ with saturated NH 4 Cl solution, 1 ⁇ with saturated NaHCO 3 solution and 1 ⁇ with saturated NaCl solution, dried on MgSO 4 , filtered, evaporated down using the rotary evaporator and Z-1b is obtained.
- A-1 may be obtained from the corresponding educts E-1 and E-2.
- Ester Z-3a (1.3 g, 3.77 mmol) is taken up in 25 mL DMSO with DIPEA (2.979 mL, 17.4 mmol) and N-methylpiperazine E-3a (0.443 mL, 4.351 mmol) is added. The reaction mixture is stirred for 20 min at 120° C. in the microwave reactor. The reaction mixture is mixed with water, the precipitate formed is filtered off, taken up in toluene, evaporated down 2 ⁇ azeotropically and Z-4a is obtained.
- Methylester Z-4-a (1.216 g, 2.98 mmol) is placed in MeOH (30 mL) and mixed at RT with an aqueous NaOH solution (5.0 mol/L, 12.146 mL, 60.73 mmol). Then the mixture is stirred overnight at 50° C. For working up the pH is adjusted to neutral by the addition of an HCl solution. The reaction mixture is extracted 2 ⁇ with water/EE (1:1), the organic phases are dried on MgSO 4 , filtered, evaporated down and Z-5a is obtained.
- Benzoic acid Z-5a (100 mg, 0.25 mmol) is taken up in DCM (5 mL) and mixed under argon with thionyl chloride (300 ⁇ L, 2.38 mmol). The reaction mixture is stirred for 1 h at RT. Then the mixture is evaporated down, dried azeotropically with dry toluene and Z-6a is obtained.
- Example compounds II differ from those of type I by an inverted amide bond between the central (hetero-)aromatic six-membered ring and the group R 2 (Reaction scheme B). These compounds are obtained analogously to the compounds I in terms of the method used, except that the reactivities are inverted accordingly in the educt components E-4 and E-5 or A-4 (compared with E-1 and E-2 or A-2).
- A (synthesis route 1 via intermediate compound Z-2).
- the components A-3 are obtained by amide coupling of the nitroanilines E-4 with carboxylic acids E-5 to obtain intermediate product Z-7 and subsequent reduction of the nitro group.
- Both the group R 1 and the group R 2 of compounds II according to the invention may be modified in other reaction steps (not shown), to obtain further compounds II according to the invention. These reaction steps may be reactions of substitution, alkylation, acylation or addition.
- P-2a (975 mg, 4.51 mmol) is taken up in DMF (25 mL) and TEA (754 ⁇ L, 5.41 mmol) is added. The reaction mixture is combined with aniline A-3a (1.327 g, 4.51 mmol) and stirred overnight at RT. For working up 100 mL ice water are added, the precipitate formed is filtered off and Z-8a is obtained.
- Z-8a (50 mg, 0.11 mmol) is taken up in DMSO (900 ⁇ L), mixed with N-methylpiperazine E-3a (32 mg, 0.32 mmol) and stirred for 15 min at 150° C. in the microwave reactor.
- the reaction mixture is purified by preparative HPLC.
- 2,8-disubstituted pyrimidopyrimidines III may also be obtained for example by the following methods (Reaction scheme C, synthesis routes 1-3).
- A-1 is used (synthesis route 1) the complete left-hand molecular part of the end compounds III is thereby introduced into the intermediate compound Z-12, so that finally there only remains the substitution in the 2-position by components R 1 —H (E-3), which are preferably primary and secondary (also cyclic) amines or alcohols (in the form of the alkoxides).
- R 1 —H preferably primary and secondary (also cyclic) amines or alcohols (in the form of the alkoxides).
- R 1 —H E-3
- the methylsulphanyl group has to be activated in the 2-position by oxidation to form the corresponding sulphoxide/sulphone for the substitution (for the synthesis of the components A-1 cf. the remarks made under Reaction scheme A).
- a mixture of the sulphoxide and sulphone is usually obtained, which is further reacted as one.
- P-3 are possible which allow successive and selective substitution, i.e. have other leaving groups.
- Both the group R 1 and the group R 2 of compounds III according to the invention may be modified in other reaction steps (not shown), to obtain other compounds III according to the invention. These reaction steps may be reactions of substitution, alkylation, acylation or addition.
- Aniline A-1b (3.3 g, 8.14 mmol) and 8-chloro-2-methylsulphanyl-pyrimido[5,4-d]pyrimidine P-3a (1.73 g, 8.14 mmol) are placed in acetic acid (20 mL) and stirred overnight at 50° C. For working up the reaction mixture is evaporated down, the residue is suspended in isopropanol/water (1:1), the precipitate formed is filtered off, dried and Z-12b is obtained.
- Z-12a (310 mg, 0.62 mmol) is taken up in DCM (5 mL). Then at RT mCPBA (70%, 183 mg, 0.74 mmol) is added and the reaction mixture is stirred for 1 h at RT. The precipitate formed is filtered off, washed with DCM, dried and Z-13a is obtained. Sulphoxide/sulphone Z-13a (90 mg, 0.174 mmol) and N-methylpiperazine E-3a (31 ⁇ L, 0.28 mmol) are placed in dioxane (0.5 mL). TEA (51 ⁇ L, 0.35 mmol) is added dropwise. The reaction mixture is stirred for 2 h at 60° C.
- Benzoic acid Z-19a (29.0 g, 88.59 mmol) is placed in glacial acetic acid (800 mL) and sodium periodate (19.139 g, 88.59 mmol) is added.
- the reaction mixture is heated for 3 h to 80° C. After cooling it is mixed with aqueous Na 2 S 2 O 5 solution (15 mL; 10%) and largely concentrated by rotary evaporation.
- Example compounds IV differ from those of type III by an inverted amide bond between the central (hetero-)aromatic six-membered ring and the group R 2 (Reaction scheme D). These compounds are obtained analogously to the compounds III in terms of the method used, except that the reactivities are inverted accordingly in the educt components E-4 and E-5 (for the synthesis of A-3, cf. Reaction scheme B) or A-4 (compared with E-1 and E-2 or A-2, cf. Reaction schemes A and C).
- the 8-position is substituted by the aniline components A-3 or A-4, preferably under basically catalysed conditions at elevated temperature.
- Both the group R 1 and the group R 2 of compounds IV according to the invention may be modified in other reaction steps (not shown), to obtain further compounds IV according to the invention. These reaction steps may be reactions of substitution, alkylation, acylation or addition.
- Z-24a (5 g, 14.47 mmol) is taken up in DCM (50 mL), combined at RT with mCPBA (3.24 g, 14.47 mmol) and stirred for 2 h at RT.
- the reaction mixture is filtered off, the filtrate is diluted with DCM and washed 3 ⁇ with saturated NaHCO 3 solution.
- the organic phase is dried on Na 2 SO 4 , filtered off, evaporated down and Z-25a is obtained.
- Z-25a is further reacted directly without any further purification (content of sulphoxide/sulphone approx. 85%).
- Z-29a (1.91 g, 4.07 mmol) is suspended in DCM (40 mL), combined at 0° C. with mCPBA (950 mg, 4.23 mmol) and stirred for 2 h at RT.
- the reaction mixture is diluted with DCM and washed 2 ⁇ with saturated NaHCO 3 solution.
- the organic phase is dried on Na 2 SO 4 , filtered off, evaporated down and Z-30a is obtained.
- Sulphoxide/sulphone Z-30a (1.39 g, 2.86 mmol) is placed in dioxane (10 mL) and mixed with TEA (1.607 mL, 11.45 mmol).
- Benzoic acid Z-34a (462 mg, 1.64 mmol) is suspended in thionyl chloride (10 mL, 134 mmol). The reaction mixture is refluxed for 1 h and stirred overnight at 60° C. The excess thionyl chloride is spun off and the remainder is dried azeotropically 1 ⁇ with toluene. The acid chloride Z-35a is used again directly.
- linker units L 2 which are different from —C(O)NH— and —NHC(O)—
- the synthesis components required may be converted routinely.
- carboxylic acids instead of carboxylic acids, sulphonic acids may be used to synthesise the corresponding sulphonamides.
- Urea linkers are obtained by reacting isocyanates with amines or the compound of two amines via a carbonylbiselectrophil (e.g. CDI, triphosgene).
- Compounds of general formula (1) are characterised by their many possible applications in the therapeutic field. Particular mention should be made of those applications in which the inhibition of specific signal enzymes, particularly the inhibiting effect on the proliferation of cultivated human tumour cells but also on the proliferation of other cells such as endothelial cells, for example, are involved.
- a dilution series 10 ⁇ L of test substance solution are placed in a multiwell plate.
- the dilution series is selected so that generally a range of concentrations of 2 ⁇ M to 0.119 nM or 0.017 nM is covered. If necessary the initial concentration of 2 ⁇ M is changed to 50 ⁇ M, 10 ⁇ M or 0.4 ⁇ M or 0.2857 ⁇ M and further dilution is carried out accordingly.
- the final concentration of DMSO is 5%.
- B-Raf (V600E)-kinase solution 10 ⁇ L of the B-Raf (V600E)-kinase solution are pipetted in (containing 0.5 ng B-Raf (V600E)-kinase in 20 mM Tris-HCl pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA, 0.286 mM sodium orthovanadate, 10% glycerol, 1 mg/mL bovine serum albumin, 1 mM dithiothreitol) and the mixture is incubated for 24 h at RT under with shaking.
- B-Raf (V600E)-kinase solution 10 ⁇ L of the B-Raf (V600E)-kinase solution are pipetted in (containing 0.5 ng B-Raf (V600E)-kinase in 20 mM Tris-HCl pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA
- the kinase reaction is started by the addition of 20 ⁇ L ATP solution [final concentration: 250 ⁇ M ATP, 30 mM Tris-HCl pH 7.5, 0.02% Brij, 0.2 mM sodium orthovanadate, 10 mM magnesium acetate, 0.1 mM EGTA, phosphatase cocktail (Sigma, # P2850, dilution recommended by the manufacturer), 0.1 mM EGTA] and 10 ⁇ L MEK1 solution [containing 50 ng biotinylated MEK1 (prepared from purified MEK1 according to standard procedure, e.g. with EZ-Link Sulpho-NHS-LC-Biotin reagent, Pierce, #21335) and carried out for 60 min at RT with constant shaking.
- 20 ⁇ L ATP solution final concentration: 250 ⁇ M ATP, 30 mM Tris-HCl pH 7.5, 0.02% Brij, 0.2 mM sodium orthovanadate, 10 mM magnesium acetate, 0.1 m
- the reaction is stopped by the addition of 12 ⁇ L of a 100 mM EDTA solution and incubation is continued for a further 5 min. 55 ⁇ L of the reaction solution are transferred into a streptavidin-coated plate (e.g. Streptawell HighBond, Roche, #11989685001) and shaken gently for 1 h at RT, in order to bind biotinylated MEK1 to the plate.
- a streptavidin-coated plate e.g. Streptawell HighBond, Roche, #11989685001
- the plate After elimination of the liquid the plate is washed five times with 200 ⁇ L of 1 ⁇ PBS and 100 ⁇ L solution of primary antibody plus europium-labelled secondary antibody [Anti Phospho-MEK (Ser217/221), Cell Signaling, #9121 and Eu-Nl labeled goat-anti-rabbit antibody, Perkin Elmer, # AD0105], the primary antibody is diluted 1:2000 and the secondary antibody is diluted to 0.4-0.5 ⁇ g/mL in Delfia Assay Buffer (Perkin Elmer, #1244-111). After 1 h shaking at RT the solution is poured away and washed five times with 200 ⁇ L Delfia Wash Buffer (Perkin Elmer, #4010-0010/#1244-114).
- Table 7 gives the IC 50 values determined for the compounds according to the invention using the above B-RAF-kinase test.
- SK-MEL-28 For measuring the proliferation of cultivated human tumour cells, cells of the melanoma cell line SK-MEL-28 [American Type Culture Collection (ATCC)] are cultivated in MEM medium, supplemented with 10% foetal calf serum, 2% sodium bicarbonate, 1 mM sodium pyruvate, 1% non-essential amino acids (e.g. from Cambrex, # BE13-114E) and 2 mM glutamine. SK-MEL28 cells are placed in 96-well flat bottomed dishes in a density of 2500 cells per well in supplemented MEM medium (see above) and incubated overnight in an incubator (at 37° C. and 5% CO 2 ).
- ATCC American Type Culture Collection
- the active substances are added to the cells in different concentrations, so that a concentration range of 50 ⁇ M to 3.2 nM is covered. If necessary the initial concentration of 50 ⁇ M is changed to 10 ⁇ M or 2 ⁇ M and further dilution is carried out accordingly (to 0.6 nM or 0.12 nM). After an incubation period of a further 72 h 20 ⁇ L AlamarBlue reagent (Serotec Ltd., # BUF012B) are added to each well and the cells are incubated for a further 3-6 h. The colour change of the AlamarBlue reagent is determined in a fluorescence spectrophotometer (e.g. Gemini, Molecular Devices). EC 50 values are calculated using a software program (GraphPadPrizm).
- cells of the melanoma cell line A375 are cultivated in DMEM medium, supplemented with 10% foetal calf serum and 2% sodium bicarbonate. Test substances are tested on A375 cells according to the procedure described for SK-MEL28 cells (see above), but seeding them at 5000 cells per well.
- the active substances are characterised in that they have a significantly lower antiproliferative effect on cell lines that do not have a B-RAF mutation, i.e. the EC 50 value is generally higher, by a factor of 10, than the EC 50 value of B-RAF mutated cell lines.
- the cellular selectivity of the active substances is demonstrated by the fact that the EC 50 value of the phospho-ERK reduction correlates with the EC 50 value of the antiproliferative activity in B-RAF mutated cell lines.
- cells of the melanoma cell line SK-MEL-28 [American Type Culture Collection (ATCC)] are cultivated in MEM medium, supplemented with 10% foetal calf serum, 2% sodium bicarbonate, 1 mM sodium pyruvate, 1% non-essential amino acids (e.g. from Cambrex, # BE13-114E) and 2 mM glutamine.
- SK-MEL28 cells are placed in 96-well flat bottomed dishes at a density of 7500 cells per well in supplemented MEM medium (see above) and incubated overnight in an incubator (at 37° C. and 5% CO 2 ).
- the active substances are added to the cells in different concentrations, so that a concentration range of 10 ⁇ M to 2.4 nM is covered. If necessary the initial concentration of 10 ⁇ M is changed to 50 ⁇ M or 2.5 ⁇ M and further dilution is carried out accordingly (to 12.2 nM or 0.6 nM). After an incubation period of a further 2 h the cells are fixed with 4% formaldehyde and rendered permeable with 0.1% Triton X-100 in PBS. Non-specific antibody binding is reduced by incubation with 5% skimmed milk powder dissolved in TBS-T. Phosphorylated ERK is detected with a mouse monoclonal anti-diphosphorylated ERK1/2 antibody (from Sigma, #M8159).
- the bound first antibody is detected by the second antibody (peroxidase coupled polyclonal rabbit anti mouse IgG from DAKO #P0161).
- the substrate TMB Peroxidase Substrate Solution from Bender MedSystems #BMS406
- the colour reaction is stopped after a few minutes with 1 M phosphoric acid.
- the colour is measured with a Spectra max Plus reader from Molecular Devices at 450 nm.
- EC 50 values are calculated using a software program (GraphPadPrizm).
- the substances of the present invention are B-RAF-kinase inhibitors.
- the inhibition of proliferation achieved by means of the compounds according to the invention is brought about above all by preventing entry into the DNA synthesis phase.
- the treated cells arrest in the G1 phase of the cell cycle.
- the compounds according to the invention are also tested on other tumour cells.
- these compounds are effective on the colon carcinoma line, e.g. Colo205, and may be used in this and other indications. This demonstrates the usefulness of the compounds according to the invention for the treatment of different types of tumours.
- Such diseases include for example: viral infections (e.g. HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukaemias, lymphomas and solid tumours (e.g. carcinomas and sarcomas), skin diseases (e.g. psoriasis); diseases based on hyperplasia which are characterised by an increase in the number of cells (e.g. fibroblasts, hepatocytes, bones and bone marrow cells, cartilage or smooth muscle cells or epithelial cells (e.g.
- viral infections e.g. HIV and Kaposi's sarcoma
- inflammatory and autoimmune diseases e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing
- bacterial, fungal and/or parasitic infections e.g. colitis, arthritis, Alzheimer's
- endometrial hyperplasia bone diseases and cardiovascular diseases (e.g. restenosis and hypertrophy). They are also suitable for protecting proliferating cells (e.g. hair, intestinal, blood and progenitor cells) from DNA damage caused by radiation, UV treatment and/or cytostatic treatment.
- proliferating cells e.g. hair, intestinal, blood and progenitor cells
- brain tumours such as for example acoustic neurinoma, astrocytomas such as pilocytic astrocytomas, fibrillary astrocytoma, protoplasmic astrocytoma, gemistocytary astrocytoma, anaplastic astrocytoma and glioblastoma, brain lymphomas, brain metastases, hypophyseal tumour such as prolactinoma, HGH (human growth hormone) producing tumour and ACTH producing tumour (adrenocorticotropic hormone), craniopharyngiomas, medulloblastomas, meningeomas and oligodendrogliomas; nerve tumours (neoplasms) such as for example tumours of the vegetative nervous system such as neuroblastoma sympathicum, ganglioneuroma, paraganglioma (pheochromocytoma, chromaffinom
- the new compounds may be used for the prevention, short-term or long-term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy or other “state-of-the-art” compounds, such as e.g. cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies.
- radiotherapy or other “state-of-the-art” compounds, such as e.g. cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies.
- the compounds of general formula (1) may be used on their own or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances.
- Chemotherapeutic agents which may be administered in combination with the compounds according to the invention, include, without being restricted thereto, hormones, hormone analogues and antihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate,
- anastrozole anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane
- LHRH agonists and antagonists e.g. goserelin acetate, luprolide
- inhibitors of growth factors growth factors such as for example “platelet derived growth factor” and “hepatocyte growth factor”, inhibitors are for example “growth factor” antibodies, “growth factor receptor” antibodies and tyrosinekinase inhibitors, such as for example cetuximab, gefitinib, imatinib, lapatinib and trastuzumab
- antimetabolites e.g.
- antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil, capecitabin and gemcitabin, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine); antitumour antibiotics (e.g. anthracyclins such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g.
- Cisplatin, oxaliplatin, carboplatin alkylation agents (e.g. Estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as for example carmustin and lomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such as for example vinblastine, vindesin, vinorelbin and vincristine; and taxanes such as paclitaxel, docetaxel); topoisomerase inhibitors (e.g.
- epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantron) and various chemotherapeutic agents such as amifostin, anagrelid, clodronat, filgrastin, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer.
- epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantron
- chemotherapeutic agents such as amifostin, anagrelid, clodronat, filgrastin, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, me
- Suitable preparations include for example tablets, capsules, suppositories, solutions—particularly solutions for injection (s.c., i.v., i.m.) and infusion—elixirs, emulsions or dispersible powders.
- the content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below.
- the doses specified may, if necessary, be given several times a day.
- Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
- excipients for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
- excipients for example inert dilu
- Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
- the core may also consist of a number of layers.
- the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
- Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
- a sweetener such as saccharine, cyclamate, glycerol or sugar
- a flavour enhancer e.g. a flavouring such as vanillin or orange extract.
- suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
- Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.
- isotonic agents e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aid
- Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
- Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
- Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers (e.g.
- pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly disper
- lignin e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone
- lubricants e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate.
- the preparations are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route.
- the tablets may, of course contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like.
- lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process.
- the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.
- solutions of the active substances with suitable liquid carriers may be used.
- the dosage for intravenous use is from 1-1000 mg per hour, preferably between 5 and 500 mg per hour.
- the finely ground active substance, lactose and some of the corn starch are mixed together.
- the mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
- the granules, the remaining corn starch and the magnesium stearate are screened and mixed together.
- the mixture is compressed to produce tablets of suitable shape and size.
- the finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened.
- the sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.
- the active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic.
- the solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion.
- the ampoules contain 5 mg, 25 mg and 50 mg of active substance.
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Abstract
Description
- The present invention relates to new compounds of general formula (1)
- wherein the groups R1 to R4, X1, X2, X3, L1 and L2 have the meanings given in the claims and specification and the tautomers, racemates, enantiomers, diastereomers and mixtures thereof and the salts of all these forms and their use as medicaments.
- Pyrimido[5,4-d]pyrimidines for inhibiting tyrosinekinases, which are involved in signal transduction, are described in WO 96/07657, WO 97/32880 and WO 97/32882.
- The aim of the present invention is to discover new active substances which can be used for the prevention and/or treatment of diseases characterised by excessive or abnormal cell proliferation.
- It has now been found that, surprisingly, compounds of general formula (1), wherein the groups R1 to R4, X1, X2, X3, L1 and L2 have the meanings given hereinafter act as inhibitors of specific signal enzymes which are involved in controlling cell proliferation. Thus, the compounds according to the invention may be used for example for the treatment of diseases connected with the activity of these signal enzymes and characterised by excessive or abnormal cell proliferation.
- The present invention therefore relates to compounds of general formula (1)
- wherein
R1 denotes hydrogen or a group optionally substituted by one or more identical or different Rb and/or Rc, selected from among C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl,
or
a suitable substituent, selected from among —ORc, —SRc, —NRcRc, —NRcNRcRc and —S(O)Rc;
R2 denotes a group optionally substituted by one or more identical or different Rb and/or Rc, selected from among C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl;
R3 is selected from among hydrogen, C1-4alkyl, halogen, —OH, —O(C1-4alkyl), —NH2, —NH(C1-4alkyl) and —N(C1-4alkyl)2;
R4 is selected from among hydrogen, —CN, —NO2, —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)2, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-5cycloalkyl and halogen;
X1, X2 and X3 are each selected independently of one another from among nitrogen and CR4*, -
- wherein at most two of the atoms X1, X2 and X3 may be nitrogen atoms and R4* are each selected independently of one another from among hydrogen, —CN, —NO2, —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)2, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-5cycloalkyl and halogen;
L1 is selected from among —CH2—, —NH—, —NMe-, —O— and —S—;
L2 is selected from among —C(O)NH—, —C(O)N(C1-4alkyl)-, —NHC(O)—, —N(C1-4alkyl)C(O)—, —CH2—NHC(O)—, —C(O)—, —C(S)NH—, —NHC(S)—, —NHCH2—, —CH2NH—, —S(O)2NH—, —NHS(O)2, —NHC(O)NH—, —OC(O)NH— and —NHC(O)O—;
each Rb is a suitable substituent and is selected independently of one another from among —ORc, —SRc, —NRcRc, —ONRcRc, —N(ORc)Rc, —NRgNRcRc, halogen, —CN, —NO2, —N3, —C(O)Rc, —C(O)ORc, —C(O)NRcRc, —C(O)NRgNRcRc, —C(O)NRgORc, —C(NRg)Rc, —N═CRcRc, —C(NRg)ORc, —C(NRg)NRcRc, —C(NRg)NRgNRcRc, —C(NORg)Rc, —C(NORg)NRcRc, —C(NNRgRg)Rc, —OS(O)Rc, —OS(O)ORc, —OS(O)NRcRc, —OS(O)2Rc, —OS(O)2ORc, —OS(O)2NRcRc, —OC(O)Rc, —OC(O)ORc, —OC(O)NRcRc, —OC(NRg)Rc, —OC(NRg)NRcRc, —ONRgC(O)Rc, —S(O)Rc, —S(O)ORc, —S(O)NRcRc, —S(O)2Rc, —S(O)2ORc, —S(O)2NRcRc, —NRgC(O)Rc, —NRgC(O)ORc, —NRgC(O)NRcRc, —NRgC(O)NRgNRcRc, —NRgC(NRg)Rc, —N═CRcNRcRc, —NRgC(NRg)ORc, —NRgC(NRg)NRcRc, —NRgC(NORg)Rc, —NRgS(O)Rc, —NRgS(O)ORc, —NRgS(O)2Rc, —NRgS(O)2ORc, —NRgS(O)2NRcRc, —NRgNRgC(O)Rc, —NRgNRgC(O)NRcRc, —NRgNRgC(NRg)Rc and —N(ORg)C(O)Rc and the bivalent substituents ═O, ═S, ═NRg, ═NORg, ═NNRgRg and ═NNRgC(O)NRgRg, while these bivalent substituents may only be substituents in non-aromatic ring systems;
each Rc independently of one another denotes hydrogen or a group optionally substituted by one or more identical or different Rd and/or Re, selected from among C1-6alkyl, 2-6 membered heteroalkyl, C1-6halo alkyl, C3-10cycloalkyl, C6-10aryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl;
each Rd is a suitable substituent and is selected independently of one another from among —ORe, —SRe, —NReRe, —ONReRe, —N(ORe)Re, —N(Rg)NReRe, halogen, —CN, —NO, —NO2, —N3, —C(O)Re, —C(O)ORe, —C(O)NReRe, —C(O)NRgNReRe, —C(O)NRgORe, —C(NRg)Re, —N═CReRe, —C(NRg)ORe, —C(NRg)NReRe, —C(NRg)NRgNReRe, —C(NORg)Re, —C(NORg)NReRe, —C(NNRgRg)Re, —OS(O)Re, —OS(O)ORe, —OS(O)NReRe, —OS(O)2Re, —OS(O)2ORe, —OS(O)2NReRe, —OC(O)Re, —OC(O)ORe, —OC(O)NReRe, —OC(NRg)Re, —OC(NRg)NReRe, —ONRgC(O)Re, —S(O)Re, —S(O)ORe, —S(O)NReRe, —S(O)2Re, —S(O)2ORe, —S(O)2NReRe, —NRgC(O)Re, —NRgC(O)ORe, —NRgC(O)NReRe, —NRgC(O)NRgNReRe, —NRgC(NRg)Re, —N═CReNReRe, —NRgC(NRg)ORe, —NRgC(NRg)NReRe, —NRgC(NRg)SRe, —NRgC(NORg)Re, —NRgS(O)Re, —NRgS(O)ORe, —NRgS(O)2Re, —NRgS(O)2ORe, NRgS(O)2NReRe, —NRgNRgC(O)Re, —NRgNRgC(O)NReRe, —NRgNRgC(NRg)Re and —N(ORg)C(O)Re and the bivalent substituents ═O, ═S, ═NRg, ═NORg, ═NNRgRg and ═NNRgC(O)NRgRg, while these bivalent substituents may only be substituents in non-aromatic ring systems;
each Re independently of one another denotes hydrogen or a group optionally substituted by one or more identical or different Rf and/or Rg, selected from among C1-6alkyl, 2-6 membered heteroalkyl, C1-6halo alkyl, C3-10cycloalkyl, C6-10aryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl;
each Rf is a suitable substituent and is selected independently of one another from among —ORg, —SRg, —NRgRg, —ONRgRg, —N(ORg)Rg, —N(Rh)NRgRg, halogen, —CN, —NO2, —N3, —C(O)Rg, —C(O)ORg, —C(O)NRgRg, —C(O)NRhNRgRg, —C(O)NRhORg, —C(NRh)Rg, —N═CRgRg, —C(NRh)ORg, —C(NRh)NRgRg, —C(NRh)NRhNRgRg, —C(NORh)Rg, —C(NORh)NRgRg, —C(NNRhRh)Rg, —OS(O)Rg, —OS(O)ORg, —OS(O)NRgRg, —OS(O)2Rg, —OS(O)2ORg, —OS(O)2NRgRg, —OC(O)Rg, —OC(O)ORg, —OC(O)NRgRg, —OC(NRh)Rg, —OC(NRh)NRgRg, —ONRhC(O)Rg, —S(O)Rg, —S(O)ORg, —S(O)NRgRg, —S(O)2Rg, —S(O)2ORg, —S(O)2NRgRg, —NRhC(O)Rg, —NRhC(O)ORg, —NRhC(O)NRgRg, —NRhC(O)NRhNRgRg, —NRhC(NRh)Rg, —N═CRgNRgRg, —NRhC(NRh)ORg, —NRhC(NRh)NRgRg, —NRhC(NORh)Rg, —NRhS(O)Rg, —NRhS(O)ORg, —NRhS(O)2Rg, —NRhS(O)2ORg, —NRhS(O)2NRgRg, —NRhNRhC(O)Rg, —NRhNRhC(O)NRgRg, —NRhNRhC(NRh)Rg and —N(ORh)C(O)Rg and the bivalent substituents ═O, ═S, ═NRh, ═NORh, ═NNRhRh and ═NNRhC(O)NRhRh, while these bivalent substituents may only be substituents in non-aromatic ring systems;
each Rg independently of one another denotes hydrogen or a group optionally substituted by one or more identical or different Rh, selected from among C1-6alkyl, 2-6 membered heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl;
each Rh is selected independently of one another from among hydrogen, C1-6alkyl, 2-6 membered heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl;
while the compounds (1) may optionally also be present in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, or also as pharmacologically acceptable salts of all the above-mentioned forms.
- wherein at most two of the atoms X1, X2 and X3 may be nitrogen atoms and R4* are each selected independently of one another from among hydrogen, —CN, —NO2, —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)2, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-5cycloalkyl and halogen;
- In one aspect (A1) the invention relates to compounds (1), wherein
- R3 denotes hydrogen.
- In another aspect (A2) the invention relates to compounds (1), wherein
- R3 denotes —NH2 or —NHMe.
- In another aspect (B1) the invention relates to compounds (1), wherein
- R1 denotes hydrogen.
- In another aspect (A1B1) the invention relates to compounds (1), wherein R1 and R3 denote hydrogen.
- In another aspect (B2) the invention relates to compounds (1), wherein
- R1 is a group optionally substituted by one or more identical or different Rb and/or R1, selected from among 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl, and Rb and Rc are as hereinbefore defined.
- In another aspect (B3) the invention relates to compounds (1), wherein
- R1 is a 3-7 membered, monocyclic and nitrogen-containing heterocycloalkyl or 6-10 membered, bicyclic and nitrogen-containing heterocycloalkyl optionally substituted by one or more identical or different Rb and/or Rc,
- R1 is bound to the pyrimido[5,4-d]pyrimidine structure through a nitrogen atom, and Rb and Rc are as hereinbefore defined.
- In another aspect (B4) the invention relates to compounds (1), wherein
- R1 is a group optionally substituted by one or more identical or different Rb and/or Rc, selected from among piperidyl, perhydro-1,4-diazepinyl, piperazinyl, octahydro-pyrrolo[1,2-c]pyrazinyl, 2,5-diazabicyclo[2,2,1]heptyl, octahydro-pyrido[1,2-c]pyrazinyl, perhydro-1,4-oxazepinyl, morpholinyl, pyrrolidinyl, perhydroazepinyl, thiomorpholinyl, thiazolidinyl and azetidinyl,
R1 is bound to the pyrimido[5,4-d]pyrimidine structure via a nitrogen atom, and Rb and Rc are as hereinbefore defined. - In another aspect (B5) the invention relates to compounds (1), wherein
- R1 is a 2-methyl-2,7-diazaspiro[4.4]nonyl optionally substituted by one or more identical or different Rb and/or Rc, which binds to the pyrimido[5,4-d]pyrimidine structure via a nitrogen atom,
and Rb and Rc are as hereinbefore defined. - In another aspect (B6) the invention relates to compounds (1) with one of the structural aspects B2 to B5,
- wherein R1 is heterocycloalkyl which is bound to the pyrimido[5,4-d]pyrimidine structure via a nitrogen atom and is optionally substituted by one or more substituents, each independently selected from among Rb1 and Rc1;
-
- each Rb1 is selected independently of one another from among —ORc1, —NRc1Rc1, halogen, —C(O)Rc1 and ═O, while the latter substituent may only be a substituent in non-aromatic ring systems,
- each Rc1 independently of one another denotes hydrogen or a group optionally substituted by one or more identical or different Rd1 and/or Re1, selected from among C1-6alkyl, phenyl, C3-10cycloalkyl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl,
- each Rd1 is selected independently of one another from among —ORe1 and —NRe1Re1,
- each Re1 independently of one another denotes hydrogen or a group optionally substituted by one or more identical or different C1-6alkyl, selected from among
- C1-6alkyl, C3-10cycloalkyl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl.
- In another aspect (B7) the invention relates to compounds (1), wherein
- R1 is selected from among
- In another aspect (B8) the invention relates to compounds (1), wherein
- R1 denotes —NRc2Rc3 and
Rc2 and Rc3 are each defined as Rc defined hereinbefore. - In another aspect (B9) the invention relates to compounds (1), wherein
- R1 denotes —NRc2Rc3 and
Rc2 is selected from among hydrogen, C1-6alkyl, C3-6cycloalkyl, phenyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl,
Rc3 is a group optionally substituted by one or more identical or different Rd3 and/or Re3, selected from among C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl and 3-14 membered heterocycloalkyl,
each Rd3 is selected independently of one another from among halogen, —NRe3Re3 and —ORe3,
each Re3 independently of one another denotes hydrogen or a group optionally substituted by one or more identical or different Rf3 and/or Rg3, selected from among C1-6alkyl, C6-10aryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl,
each Rf3 denotes —ORg3 and
each Rg3 are each selected independently of one another from among hydrogen and C1-6alkyl. - In another aspect (B10) the invention relates to compounds (1) with one of the structural aspects B8 or B9, wherein
- Rc2 denotes hydrogen.
- In another aspect (B11) the invention relates to compounds (1), wherein
- R1 is selected from among
- In another aspect (B12) the invention relates to compounds (1) with one of the structural aspects B8 or B9, wherein
- Rc2 denotes methyl or ethyl.
- In another aspect (B13) the invention relates to compounds (1), wherein
- R1 is selected from among
- In another aspect (C1) the invention relates to compounds (1), wherein
- R4 denotes fluorine, bromine, chlorine or methyl.
- In another aspect (D1) the invention relates to compounds (1), wherein
- X1 denotes CR4*-1, X2 denotes CR4*-2 and X3 denotes CR4*-3 and
-
- R4*-1, R4*-2 and R4*-3 are each selected from among hydrogen, fluorine, chlorine and methyl and at least two of the groups R4*-1, R4*-2 and R4*-3 denote hydrogen.
- In another aspect (D2) the invention relates to compounds (1), wherein
- X1, X2 and X3 each denote CH.
- In another aspect (D3) the invention relates to compounds (1), wherein
- X1 denotes nitrogen, X2 denotes CR4*-2 and X3 denotes CR4*-3 and R4*-2 and R4*-3 are each selected from among hydrogen, fluorine, bromine, chlorine and methyl and at least one of the groups R4*-2 and R4*-3 denotes hydrogen.
- In another aspect (D4) the invention relates to compounds (1), wherein
- X1 denotes nitrogen, X2 denotes CH and X3 denotes CH.
- In another aspect (E1) the invention relates to compounds (1), wherein
- L1 denotes —NH— or —NMe-.
- In another aspect (F1) the invention relates to compounds (1), wherein
- R2 is a group optionally substituted by one or more identical or different Rb and/or Rc, selected from among C6-10aryl and 5-12 membered heteroaryl,
and Rb and Rc are as hereinbefore defined. - In another aspect (F2) the invention relates to compounds (1), wherein
- R2 is a group optionally substituted by one or more identical or different Rb and/or Rc, selected from among phenyl and 5-6 membered heteroaryl, and Rb and Rc are as hereinbefore defined.
- In another aspect (F3) the invention relates to compounds (1), wherein
- R2 is a 5-6 membered heteroaryl optionally substituted by one or more identical or different Rb and/or Rc
and Rb and Rc are as hereinbefore defined. - In another aspect (F4) the invention relates to compounds (1),
- wherein R2 is a heteroaryl which is selected from among furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, triazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl and pyrimidyl, and is optionally substituted by one or two substituents, each independently selected from among C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, 1-methylbutyl, 1-ethylpropyl, isopentyl, neopentyl, trifluoromethyl, difluoromethyl, fluoromethyl, tert.-butoxy, trifluoromethoxy,
- In another aspect (F5) the invention relates to compounds (1), wherein
- R2 is a phenyl optionally substituted by one or more identical or different Rb and/or Rc, and Rb and Rc are as hereinbefore defined.
- In another aspect (F6) the invention relates to compounds (1), wherein
- R2 denotes a phenyl
-
- R5 is selected from among hydrogen, C1-6alkyl, —OC1-6alkyl, C1-6haloalkyl, —OC1-6haloalkyl, C3-7cycloalkyl and 3-7 membered heterocycloalkyl, all the above-mentioned groups optionally being substituted by C1-6alkyl, —CN or —OH;
- R6 is selected from among hydrogen, C1-6alkyl, —OC1-6alkyl, C1-6haloalkyl, —OC1-6haloalkyl, —CN, —OH, halogen, —NHC1-6alkyl and —N(C1-6alkyl)2, the latter two optionally being substituted in the alkyl moiety by a substituent —N(C1-6alkyl)2;
- R7 is selected from among hydrogen, —OC1-6alkyl, halogen, —NHS(O)2C1-6alkyl, —S(O)2NH2, —S(O)2NHC1-6alkyl, —S(O)2N(C1-6alkyl)2,
-
-
- R9 is selected from among hydrogen and C1-6alkyl;
- Rc4 is hydrogen or a group optionally substituted by one or more identical or different Rd4 and/or Re4, selected from among C1-6alkyl and 3-14 membered heterocycloalkyl;
- each Rd4 is a suitable substituent and is selected independently of one another from among —ORe4, —NRe4Re4 and halogen;
- each Re4 independently of one another denotes hydrogen or a group optionally substituted by one or more identical or different Rf4 and/or Rg4, selected from among C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl;
- each Rf4 is a suitable substituent and is selected independently of one another from among —ORg4, —NRg4Rg4 and halogen as well as the bivalent substituent ═O, which may only be a substituent in non-aromatic ring systems;
- each Rg4 independently of one another denotes hydrogen or a group optionally substituted by one or more identical or different Rh4, selected from among C1-6alkyl, C3-10cycloalkyl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl;
- each Rh4 is selected independently of one another from among C1-6alkyl and the bivalent substituent ═O, which may only be a substituent in non-aromatic ring systems;
- or
- the group —NRgRe4 denotes a nitrogen-containing, 3-14 membered heterocycloalkyl or 5-12 membered heteroaryl, optionally substituted by one or more identical or different group(s) selected from among Rd4 and Re4;
- the group —NRgRe4 denotes a nitrogen-containing, 3-14 membered heterocycloalkyl or 5-12 membered heteroaryl, optionally substituted by one or more identical or different group(s) selected from among Rf4 and Rg4;
- the group —NRgRg4 denotes a nitrogen-containing 3-14 membered heterocycloalkyl or 5-12 membered heteroaryl, optionally substituted by one or more identical or different group(s) Rh4; and
- R8 is selected from among hydrogen, C1-6alkyl, —OC1-6alkyl, —CN, halogen, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl.
-
- In another aspect (F7) the invention relates to compounds (1) with structural aspect F6, wherein
- at least one of the groups R5 to R8 is not hydrogen.
- In another aspect (F8) the invention relates to compounds (1) with structural aspect F6, wherein
- R5 is selected from among
- In another aspect (F9) the invention relates to compounds (1), wherein
- R2 is selected from among
- and R′ denotes the binding site to the linker unit L2.
- In another aspect (F10) the invention relates to compounds (1), wherein
- R2 is selected from among
- and R′ denotes the binding site to the linker unit L2.
- In another aspect (F11) the invention relates to compounds (1), wherein
- R2 is selected from among
- and R′ denotes the binding site to the linker unit L2.
- In another aspect (G1) the invention relates to compounds (1), wherein
- L2 denotes (R2)—NHC(O)—.
- In another aspect (G2) the invention relates to compounds (1), wherein
- L2 denotes (R2)—C(O)NH—.
- All the above-mentioned structural aspects A to G relating to different molecular parts of the compounds (1) according to the invention may be permutated with one another as desired to form combinations ABCDEFG, so as to obtain preferred compounds (1). Each combination ABCDEFG represents and defines individual embodiments or generic partial amounts of compounds according to the invention. Every individual embodiment or partial amount defined by this combination is expressly included and is an object of the invention.
- In another aspect the invention relates to compounds—or the pharmacologically acceptable salts thereof—of general formula (1) as medicaments.
- In another aspect the invention relates to pharmaceutical preparations, containing as active substance one or more compounds of general formula (1) or the pharmacologically acceptable salts thereof, optionally in combination with conventional excipients and/or carriers.
- In another aspect the invention relates to compounds of general formula (1) for use in the treatment and/or prevention of cancer, infections, inflammations and autoimmune diseases.
- In another aspect the invention relates to compounds of general formula (1) for use in the treatment and/or prevention of cancer.
- In another aspect the invention relates to a pharmaceutical preparation comprising a compound of general formula (1), while the compounds (1) may optionally also be in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof or as the respective pharmacologically acceptable salts of all the above-mentioned forms, and at least one other cytostatic or cytotoxic active substance different from formula (1).
- As used herein, the following definitions apply, unless stated otherwise:
- The use of the prefix Cx-y, where x and y in each case denote a natural number (x<y), indicates that the chain or cyclic structure or combination of chain and cyclic structure referred to and mentioned in direction connection may consist in total of a maximum of y and a minimum of x carbon atoms.
- The information as to the number of members in groups containing one or more hetero-atom(s) (heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl) refers to the total atomic number of all the ring members or chain members or the total of all the ring and chain members.
- Alkyl is made up of the sub-groups saturated hydrocarbon chains and unsaturated hydrocarbon chains, while the latter may be further subdivided into hydrocarbon chains with a double bond (alkenyl) and hydrocarbon chains with a triple bond (alkynyl). Alkenyl contains at least one double bond, alkynyl at least one triple bond. If a hydrocarbon chain should have both at least one double bond and at least one triple bond, by definition it belongs to the alkynyl sub-group. All the above-mentioned sub-groups may be further subdivided into straight-chain (unbranched) and branched. If an alkyl is substituted, it may be mono- or polysubstituted independently of one another at all the hydrogen-carrying carbon atoms. Examples of individual sub-groups are listed below:
-
- methyl; ethyl; n-propyl; isopropyl (1-methylethyl); n-butyl; 1-methylpropyl; isobutyl (2-methylpropyl); sec.-butyl (1-methylpropyl); tert.-butyl (1.1-dimethylethyl); n-pentyl; 1-methylbutyl; 1-ethylpropyl; isopentyl (3-methylbutyl); neopentyl (2,2-dimethyl-propyl); n-hexyl; 2,3-dimethylbutyl; 2,2-dimethylbutyl; 3,3-dimethylbutyl; 2-methyl-pentyl; 3-methylpentyl; n-heptyl; 2-methylhexyl; 3-methylhexyl; 2,2-dimethylpentyl; 2,3-dimethylpentyl; 2,4-dimethylpentyl; 3,3-dimethylpentyl; 2,2,3-trimethylbutyl; 3-ethylpentyl; n-octyl; n-nonyl; n-decyl etc.
-
- vinyl (ethenyl); prop-1-enyl; allyl (prop-2-enyl); isopropenyl; but-1-enyl; but-2-enyl; but-3-enyl; 2-methyl-prop-2-enyl; 2-methyl-prop-1-enyl; 1-methyl-prop-2-enyl; 1-methyl-prop-1-enyl; 1-methylidenepropyl; pent-1-enyl; pent-2-enyl; pent-3-enyl; pent-4-enyl; 3-methyl-but-3-enyl; 3-methyl-but-2-enyl; 3-methyl-but-1-enyl; hex-1-enyl; hex-2-enyl; hex-3-enyl; hex-4-enyl; hex-5-enyl; 2,3-dimethyl-but-3-enyl; 2,3-dimethyl-but-2-enyl; 2-methylidene-3-methylbutyl; 2,3-dimethyl-but-1-enyl; hexa-1,3-dienyl; hexa-1,4-dienyl; penta-1,4-dienyl; penta-1,3-dienyl; buta-1,3-dienyl; 2,3-dimethylbuta-1,3-diene etc.
-
- ethynyl; prop-1-ynyl; prop-2-ynyl; but-1-ynyl; but-2-ynyl; but-3-ynyl; 1-methyl-prop-2-ynyl etc.
- By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl etc. unless otherwise stated are meant saturated hydrocarbon groups with the corresponding number of carbon atoms, including all the isomeric forms.
- By the terms propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl etc. unless otherwise stated are meant unsaturated hydrocarbon groups with the corresponding number of carbon atoms and a double bond, including all the isomeric forms, also (Z)/(E)-isomers, where applicable.
- By the terms butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl etc. unless otherwise stated are meant unsaturated hydrocarbon groups with the corresponding number of carbon atoms and two double bonds, including all the isomeric forms, also (Z)/(E)-isomers, where applicable.
- By the terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl etc. unless otherwise stated are meant unsaturated hydrocarbon groups with the corresponding number of carbon atoms and a triple bond, including all the isomeric forms.
- From alkyl as hereinbefore defined and its subgroups the term alkylene can also be derived. Alkylene unlike alkyl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from an alkyl. Corresponding groups are for example —CH3 and —CH2, —CH2CH3 and —CH2CH2 or >CHCH3 etc. For all the subgroups of alkyl there are correspondences for alkylene.
- By heteroatoms are meant oxygen, nitrogen and sulphur atoms.
- By the term heteroalkyl are meant groups which are derived from the alkyl as hereinbefore defined in its widest sense by replacing, in the hydrocarbon chains, one or more of the groups —CH3 independently of one another by the groups —OH, —SH or —NH2, one or more of the groups —CH2— independently of one another by the groups —O—, —S— or —NH—, one or more of the groups >CH— by the group >N—, one or more of the groups ═CH— by the group ═N—, one or more of the groups ═CH2 by the group ═NH or one or more of the groups ≡CH by the group ≡N, while a total of not more than three heteroatoms may be present in one heteroalkyl, there must be at least one carbon atom between two oxygen atoms and between two sulphur atoms or between one oxygen and one sulphur atom and the group as a whole must have chemical stability.
- A direct result of the indirect definition/derivation from alkyl is that heteroalkyl is made up of the sub-groups saturated hydrocarbon chains with heteroatom(s), heteroalkenyl and heteroalkynyl, and it may be further subdivided into straight-chain (unbranched) and branched. If a heteroalkyl is substituted, it may be mono- or polysubstituted independently of one another at all the hydrogen-carrying oxygen, sulphur, nitrogen and/or carbon atoms. Heteroalkyl itself as a substituent may be attached to the molecule both through a carbon atom and through a heteroatom. The following are listed by way of example:
- dimethylaminomethyl; dimethylaminoethyl (1-dimethylaminoethyl; 2-dimethyl-amino-ethyl); dimethylaminopropyl (1-dimethylaminopropyl, 2-dimethylaminopropyl, 3-dimethylaminopropyl); diethylaminomethyl; diethylaminoethyl (1-diethylamino ethyl, 2-diethylamino ethyl); diethylaminopropyl (1-diethylaminopropyl, 2-diethylamino-propyl, 3-diethylaminopropyl); diisopropylaminoethyl (1-diisopropylaminoethyl, 2-diisopropyl-aminoethyl); bis-2-methoxyethylamino; [2-(dimethylamino-ethyl)-ethyl-amino]-methyl; 3-[2-(dimethylamino-ethyl)-ethyl-amino]-propyl; hydroxymethyl; 2-hydroxy-ethyl; 3-hydroxypropyl; methoxy; ethoxy; propoxy; methoxymethyl; 2-methoxyethyl etc.
- From heteroalkyl as hereinbefore defined and its subgroups the term heteroalkylene can also be derived. Heteroalkylene unlike heteroalkyl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from a heteroalkyl. Corresponding groups are for example —CH2NH2 and —CH2NH— or >CHNH2, —NHCH3 and >NCH3 or —NHCH2—, —CH2OCH3 and —CH2OCH2— or >CHOCH3 etc. For all the subgroups of heteroalkyl there are correspondences for heteroalkylene.
- Haloalkyl is derived from alkyl as hereinbefore defined in its broadest sense, by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different. A direct result of the indirect definition/derivation from alkyl is that haloalkyl is made up of the sub-groups saturated hydrohalogen chains, haloalkenyl and haloalkynyl, and it may be further subdivided into straight-chain (unbranched) and branched. If a haloalkyl is substituted, it may be mono- or polysubstituted independently of one another at all the hydrogen-carrying carbon atoms. Typical examples are listed below:
- —CF3; —CHF2; —CH2F; —CF2CF3; —CHFCF3; —CH2CF3; —CF2CH3; —CHFCH3; —CF2CF2CF3; —CF2CH2CH3; —CF═CF2; —CCl═CH2; —CBr═CH2; —CI═CH2; —C≡C—CF3; —CHFCH2CH3; —CHFCH2CF3 etc.
- From haloalkyl as hereinbefore defined and its subgroups the term haloalkylene can also be derived. Haloalkylene unlike haloalkyl is bivalent and requires two bonding partners.
- Formally the second valency is produced by removing a hydrogen atom from a haloalkyl. Corresponding groups are for example —CH2F and —CHF—, —CHFCH2F and —CHFCHF— or >CFCH2F etc. For all the subgroups of haloalkyl there are correspondences for haloalkylene.
- Halogen encompasses fluorine, chlorine, bromine and/or iodine atoms.
- Cycloalkyl is made up of the sub-groups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spirohydrocarbon rings, while each sub-group may be further subdivided into saturated and unsaturated (cycloalkenyl). By unsaturated is meant that there is at least one double bond in the ring system, but no aromatic system is formed. In bicyclic hydrocarbon rings two rings are linked such that they share at least two carbon atoms. In spirohydrocarbon rings one carbon atom (spiroatom) is shared by two rings. If a cycloalkyl is substituted, it may be mono- or polysubstituted independently of one another at all the hydrogen-carrying carbon atoms. Cycloalkyl itself as a substituent may be attached to the molecule through any suitable position of the ring system. The following individual sub-groups are listed by way of example:
-
- cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cycloheptyl etc.
Monocyclic hydrocarbon rings, unsaturated: - cycloprop-1-enyl; cycloprop-2-enyl; cyclobut-1-enyl; cyclobut-2-enyl; cyclopent-1-enyl; cyclopent-2-enyl; cyclopent-3-enyl; cyclohex-1-enyl; cyclohex-2-enyl; cyclohex-3-enyl; cyclohept-1-enyl; cyclohept-2-enyl; cyclohept-3-enyl; cyclohept-4-enyl; cyclobuta-1,3-dienyl; cyclopenta-1,4-dienyl; cyclopenta-1,3-dienyl; cyclopenta-2,4-dienyl; cyclohexa-1,3-dienyl; cyclohexa-1,5-dienyl; cyclohexa-2,4-dienyl; cyclohexa-1,4-dienyl; cyclohexa-2,5-dienyl etc.
-
- bicyclo[2.2.0]hexyl; bicyclo[3.2.0]heptyl; bicyclo[3.2.1]octyl; bicyclo[2.2.2]octyl; bicyclo[4.3.0]nonyl (octahydroindenyl); bicyclo[4.4.0]decyl (decahydronaphthalene); bicyclo[2.2.1]heptyl (norbornyl); (bicyclo[2.2.1]hepta-2,5-dienyl (norborna-2,5-dienyl); bicyclo[2.2.1]hept-2-enyl (norbornenyl); bicyclo[4.1.0]heptyl (norcaranyl); bicyclo-[3.1.1]heptyl (pinanyl) etc.
- Spirohydrocarbon Rings (Saturated and Unsaturated):
- spiro[2.5]octyl, spiro[3.3]heptyl, spiro[4.5]dec-2-ene, etc.
- If the free valency of a cycloalkyl is saturated off, an alicyclic ring is obtained.
- From cycloalkyl as hereinbefore defined and its subgroups the term cycloalkylene can also be derived. Cycloalkylene unlike cycloalkyl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from a cycloalkyl. Corresponding groups are for example cyclohexyl and
- cyclopentenyl and
- etc.
- For all the subgroups of cycloalkyl there are correspondences for cycloalkylene.
- Cycloalkylalkyl refers to the combination of the alkyl in question, as hereinbefore defined, with cycloalkyl, both in their widest sense. Alternatively cycloalkylalkyl may also be regarded as a combination of cycloalkyl with alkylene. Formally, cycloalkylalkyl is obtained by first linking an alkyl as substituent directly with the molecule and then substituting with a cycloalkyl. The linking of alkyl and cycloalkyl may be carried out in both groups using carbon atoms that are suitable for this purpose. The respective subgroups of alkyl (alkylene) and cycloalkyl are also included in the combination of the two groups.
- Aryl denotes mono-, bi- or tricyclic carbon rings with at least one aromatic ring. If an aryl is substituted, the substitution may be mono- or polysubstitution in each case, at all the hydrogen-carrying carbon atoms, independently of one another. Aryl itself may be linked to the molecule as substituent via any suitable position of the ring system. Typical examples are listed below:
- phenyl, naphthyl, indanyl (2,3-dihydroindenyl), 1,2,3,4-tetrahydronaphthyl; fluorenyl, etc.
- If the free valency of an aryl is saturated off, an aromatic group is obtained.
- From aryl as hereinbefore defined the term arylene can also be derived. Arylene unlike aryl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from an aryl. Corresponding groups are for example phenyl and
- naphthyl and
- etc. For all the subgroups of aryl there are correspondences for arylene.
- Arylalkyl denotes the combination of the groups alkyl and aryl as hereinbefore defined, in each case in their broadest sense. Alternatively arylalkyl may also be regarded as a combination of aryl with alkylene. Formally, arylalkyl is obtained by first linking an alkyl as substituent directly to the molecule and substituting it with an aryl group. The alkyl and aryl may be linked in both groups via any carbon atoms suitable for this purpose. The respective sub-groups of alkyl (alkylene) and aryl are also included in the combination of the two groups. Typical examples are listed below:
- benzyl; 1-phenylethyl; 2-phenylethyl; phenylvinyl; phenylallyl etc.
- Heteroaryl denotes monocyclic aromatic rings or polycyclic rings with at least one aromatic ring, which, compared with corresponding aryl or cycloalkyl, contain instead of one or more carbon atoms one or more identical or different heteroatoms, selected independently of one another from among nitrogen, sulphur and oxygen, while the resulting group must be chemically stable. The prerequisite for the presence of heteroaryl is a heteroatom and an aromatic system, although it need not necessarily be a heteroaromatic system. Thus 2,3-dihydro-1H-indol-6-yl
- may according to the definition be a heteroaryl.
- If a heteroaryl is substituted, the substitution may be mono- or polysubstitution in each case, at all the hydrogen-carrying carbon and/or nitrogen atoms, independently of one another. Heteroaryl itself as substituent may be linked to the molecule via any suitable position of the ring system, both carbon and nitrogen. Typical examples are listed below.
-
- furyl; thienyl; pyrrolyl; oxazolyl; thiazolyl; isoxazolyl; isothiazolyl; pyrazolyl; imidazolyl; triazolyl; tetrazolyl; oxadiazolyl; thiadiazolyl; pyridyl; pyrimidyl; pyridazinyl; pyrazinyl; triazinyl; pyridyl-N-oxide; pyrrolyl-N-oxide; pyrimidinyl-N-oxide; pyridazinyl-N-oxide; pyrazinyl-N-oxide; imidazolyl-N-oxide; isoxazolyl-N-oxide; oxazolyl-N-oxide; thiazolyl-N-oxide; oxadiazolyl-N-oxide; thiadiazolyl-N-oxide; triazolyl-N-oxide; tetrazolyl-N-oxide etc.
-
- indolyl; isoindolyl; benzofuryl; benzothienyl; benzoxazolyl; benzothiazolyl; benzisoxazolyl; dihydroindolyl; benzisothiazolyl; benzimidazolyl; indazolyl; isoquinolinyl; quinolinyl; quinoxalinyl; cinnolinyl; phthalazinyl; quinazolinyl; benzotriazinyl; indolizinyl; oxazolopyridyl; imidazopyridyl; naphthyridinyl; indolinyl; isochromanyl; chromanyl; tetrahydroisoquinolinyl; isoindolinyl; isobenzotetrahydrofuryl; isobenzotetrahydrothienyl; isobenzothienyl; benzoxazolyl; pyridopyridyl; benzotetrahydrofuryl; benzotetrahydro-thienyl; purinyl; benzodioxolyl; phenoxazinyl; phenothiazinyl; pteridinyl; benzothiazolyl; imidazopyridyl; imidazothiazolyl; dihydrobenzisoxazinyl; benzisoxazinyl; benzoxazinyl; dihydrobenzisothiazinyl; benzopyranyl; benzothiopyranyl; coumarinyl; isocoumarinyl; chromonyl; chromanonyl; tetrahydroquinolinyl; dihydroquinolinyl; dihydroquinolinonyl; dihydroisoquinolinonyl; dihydrocoumarinyl; dihydroisocoumarinyl; isoindolinonyl; benzodioxanyl; benzoxazolinonyl; quinolinyl-N-oxide; indolyl-N-oxide; indolinyl-N-oxide; isoquinolyl-N-oxide; quinazolinyl-N-oxide; quinoxalinyl-N-oxide; phthalazinyl-N-oxide; indolizinyl-N-oxide; indazolyl-N-oxide; benzothiazolyl-N-oxide; benzimidazolyl-N-oxide; benzothiopyranyl-5-oxide and benzothiopyranyl-S,S-dioxide etc.
- If the free valency of a heteroaryl is saturated off, a heteroaromatic group is obtained.
- From heteroaryl as hereinbefore defined the term heteroarylene can also be derived. Heteroarylene unlike heteroaryl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from a heteroaryl.
- Corresponding groups are for example pyrrolyl and
- 2,3-dihydro-1H-indolyl and
- etc.
- For all the subgroups of heteroaryl there are correspondences for heteroarylene.
- Heteroarylalkyl denotes the combination of the alkyl in question as hereinbefore defined with heteroaryl, both in their broadest sense. Alternatively heteroarylalkyl may also be regarded as a combination of heteroaryl with alkylene. Formally heteroarylalkyl is obtained by first linking an alkyl as substituent directly with the molecule and then substituting it with a heteroaryl. The linking of the alkyl and heteroaryl may be achieved on the alkyl side via any carbon atoms suitable for this purpose and on the heteroaryl side via any carbon or nitrogen atoms suitable for this purpose. The respective sub-groups of alkyl (alkylene) and heteroaryl are also included in the combination of the two groups.
- By the term heterocycloalkyl are meant groups which are derived from the cycloalkyl as hereinbefore defined if in the hydrocarbon rings one or more of the groups —CH2— are replaced independently of one another by the groups —O—, —S— or —NH— or one or more of the groups ═CH— are replaced by the group ═N—, while not more than five heteroatoms may be present in total, there must be at least one carbon atom between two oxygen atoms and between two sulphur atoms or between one oxygen and one sulphur atom and the group as a whole must be chemically stable. Heteroatoms may simultaneously be present in all the possible oxidation stages (sulphur→sulphoxide —SO—, sulphone —SO2—; nitrogen→N-oxide). It is immediately apparent from the indirect definition/derivation from cycloalkyl that heterocycloalkyl is made up of the sub-groups monocyclic hetero-rings, bicyclic hetero-rings and spirohetero-rings, while each sub-group can also be further subdivided into saturated and unsaturated (heterocycloalkenyl). The term unsaturated means that in the ring system in question there is at least one double bond, but no aromatic system is formed. In bicyclic hetero-rings two rings are linked such that they have at least two atoms in common. In spirohetero-rings one carbon atom (spiroatom) is shared by two rings. If a heterocycloalkyl is substituted, the substitution may be mono- or polysubstitution in each case, at all the hydrogen-carrying carbon and/or nitrogen atoms, independently of one another. Heterocycloalkyl itself as substituent may be linked to the molecule via any suitable position of the ring system. Typical examples of individual sub-groups are listed below.
-
- tetrahydrofuryl; pyrrolidinyl; pyrrolinyl; imidazolidinyl; thiazolidinyl; imidazolinyl; pyrazolidinyl; pyrazolinyl; piperidinyl; piperazinyl; oxiranyl; aziridinyl; azetidinyl; 1,4-dioxanyl; azepanyl; diazepanyl; morpholinyl; thiomorpholinyl; homomorpholinyl; homopiperidinyl; homopiperazinyl; homothiomorpholinyl; thiomorpholinyl-5-oxide; thiomorpholinyl-S,S-dioxide; 1,3-dioxolanyl; tetrahydropyranyl; tetrahydrothiopyranyl; [1,4]-oxazepanyl; tetrahydrothienyl; homothiomorpholinyl-S,S-dioxide; oxazolidinonyl; dihydropyrazolyl; dihydropyrrolyl; dihydropyrazinyl; dihydropyridyl; dihydropyrimidinyl; dihydrofuryl; dihydropyranyl; tetrahydrothienyl-5-oxide; tetrahydrothienyl-S,S-dioxide; homothiomorpholinyl-5-oxide; 2,3-dihydroazet; 2H-pyrrolyl; 4H-pyranyl; 1,4-dihydropyridinyl etc.
-
- 8-azabicyclo[3.2.1]octyl; 8-azabicyclo[5.1.0]octyl; 2-oxa-5-azabicyclo[2.2.1]heptyl; 8-oxa-3-aza-bicyclo[3.2.1]octyl; 3,8-diaza-bicyclo[3.2.1]octyl; 2,5-diaza-bicyclo-[2.2.1]heptyl; 1-aza-bicyclo[2.2.2]octyl; 3,8-diaza-bicyclo[3.2.1]octyl; 3,9-diaza-bicyclo[4.2.1]nonyl; 2,6-diaza-bicyclo[3.2.2]nonyl etc.
-
- 1,4-dioxa-spiro[4.5]decyl; 1-oxa-3.8-diaza-spiro[4.5]decyl; and 2,6-diaza-spiro[3.3]heptyl; 2,7-diaza-spiro[4.4]nonyl; 2,6-diaza-spiro[3.4]octyl; 3,9-diaza-spiro[5.5]undecyl; 2,8-diaza-spiro[4.5]decyl etc.
- If the free valency of a heterocycloalkyl is saturated off, then a heterocyclic ring is obtained.
- From heterocycloalkyl as hereinbefore defined the term heterocycloalkylene can also be derived. Heterocycloalkylene unlike heterocycloalkyl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from a heterocycloalkyl. Corresponding groups are for example piperidinyl and
- 2,3-dihydro-1H-pyrrolyl and
- etc. For all the subgroups of heterocycloalkyl there are correspondences for heterocycloalkylene.
- Heterocycloalkylalkyl denotes the combination of the alkyl in question as hereinbefore defined with heterocycloalkyl, both in their broadest sense. Alternatively heterocycloalkylalkyl may also be regarded as a combination of heterocycloalkyl with alkylene. Formally heterocycloalkyl is obtained by first linking an alkyl as substituent directly with the molecule and then substituting it with a heterocycloalkyl. The linking of the alkyl and heterocycloalkyl may be achieved on the alkyl side via any carbon atoms suitable for this purpose and on the heterocycloalkyl side via any carbon or nitrogen atoms suitable for this purpose. The respective sub-groups of alkyl and heterocycloalkyl are also included in the combination of the two groups.
- By is substituted is meant that a hydrogen atom that is bound directly to the atom under consideration is replaced by another atom or another group of atoms (substituent). Depending on the starting conditions (number of hydrogen atoms) mono- or polysubstitution may take place at an atom.
- Bivalent substituents such as for example ═S, ═NR, ═NOR, ═NNRR, ═NN(R)C(O)NRR, ═N2 or the like may only be substituents at carbon atoms, while the bivalent substituent ═O may also be a substituent of sulphur. Generally speaking, substitution by a bivalent substituent may only take place at ring systems and requires exchange for two geminal hydrogen atoms, i.e. hydrogen atoms that are bound to the same carbon atom saturated before the substitution. Substitution by a bivalent substituent is therefore only possible at the group —CH2— or sulphur atoms of a ring system.
- In addition to this, the term “suitable substituent” denotes a substituent which on the one hand is suitable on account of its valency and on the other hand leads to a system with chemical stability.
- The following are some abbreviated notations and their structural correspondences:
- If for example in the sequence A-B—C the member B were to correspond to the structural detail —N═, this is to be understood as both A=N—C and
- A-N═C
- If for example in the sequence
- the member A were to correspond to the structural detail >C═
this is to be understood as being - In a diagram such as for example
- the dotted line indicates that the ring system may be attached to the molecule via the carbon 1 or 2, i.e. is equivalent to the following diagram
- For bivalent groups where the valency with which they bind which adjacent group is critical, the corresponding binding partners are given in brackets, wherever it is necessary for clarification, as in the following formulae:
- Groups or substituents are frequently selected from among alternative groups/substituents with a corresponding group designation (e.g. Ra, Rb etc). If a group of this kind is used repeatedly to define a compound according to the invention in different parts of the molecule, it should always be borne in mind that the respective uses are to be regarded as being totally independent of one another.
-
-
Ac acetyl ATP adenosine triphosphate Bn benzyl Boc tert.-butyloxycarbonyl Bu butyl c concentration chex cyclohexane d day(s) TLC thin layer chromatography DCM dichloromethane DEA diethylamine DIPEA N-ethyl-N,N-diisopropylamine (HÜNIG base) DMAP 4-N,N-dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulphoxide DPPA diphenylphosphorylazide EDTA ethylenediaminetetraacetic acid EE ethyl acetate EGTA ethyleneglycoltetraacetic acid eq equivalent(s) ESI electron spray ionization Et ethyl Et2O diethyl ether EtOH ethanol h hour HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl- uronium hexafluorophosphate hex hexyl HPLC high performance liquid chromatography Hünig base N-ethyl-N,N-diisopropylamine i iso cat. catalyst, catalytically conc. concentrated LC liquid chromatography sln. solution mCPBA meta-chloroperbenzoic acid Me methyl MeOH methanol min minutes MPLC medium pressure liquid chromatography MS mass spectrometry NMP N-methylpyrrolidone NP normal phase n.a. not available PBS phosphate-buffered saline Ph phenyl PMSF benzylsulphonic acid fluoride Pr propyl Py pyridine rac racemic red. reduction Rf (Rf) retention factor RP reversed phase RT room temperature SN nucleophilic substitution TBAF tetrabutylammonium fluoride TBME tert-butylmethylether TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium tetrafluoroborate TEA triethylamine temp. temperature tert. tertiary Tf triflate TFA trifluoroacetic acid THF tetrahydrofuran TMS trimethylsilyl tRet. retention time (HPLC) TRIS tris(hydroxymethyl)-aminomethane TsOH para-toluenesulphonic acid UV ultraviolet - Features and advantages of the present invention will become apparent from the following detailed Examples, which illustrate the fundamentals of the invention by way of example, without restricting its scope:
- Unless stated otherwise, all the reactions are carried out in commercially obtainable apparatus using methods that are commonly used in chemical laboratories. Starting materials that are sensitive to air and/or moisture are stored under protective gas and corresponding reactions and manipulations therewith are carried out under protective gas (nitrogen or argon).
- Microwave reactions are carried out in an initiator/reactor made by Biotage or in an Explorer made by CEM in sealed containers (preferably 2, 5 or 20 mL), preferably with stirring.
- For preparative medium pressure chromatography (MPLC, normal phase) silica gel made by Millipore (name: Granula Silica Si-60A 35-70 μm) or C-18 RP-silica gel (RP-phase) made by Macherey Nagel (name: Polygoprep 100-50 C18) is used. Automated normal phase chromatography is also carried out on a CombiFlash Companion XL apparatus in combination with a CombiFlash Foxy 200 fraction collector made by Isco.
- For this, commercially obtainable RediSepRf (120 g silica gel) one-way columns are used. The thin layer chromatography is carried out on ready-made silica gel 60 TLC plates on glass (with fluorescence indicator F-254) made by Merck.
- The preparative high pressure chromatography (HPLC) of the example compounds according to the invention is carried out with columns made by Waters (names: XTerra Prep. MS C18, 5 μm, 30×100 mm or XTerra Prep. MS C18, 5 μm, 50×100 mm OBD or Symmetrie C18, 5 μm, 19×100 mm or Sunfire C18 OBD, 19×100 mm, 5 μm or Sunfire Prep C 10 μm OBD 50×150 mm or X-Bridge Prep C18 5 μm OBD 19×50 mm), Agilent (name: Zorbax SB-C8 5μm PrepHT 21.2×50 mm) and Phenomenex (names: Gemini C18 5 μm AXIA 21.2×50 mm or Gemini C18 10 μm 50×150 mm). Different gradients of H2O/acetonitrile or H2O/MeOH are used to elute the compounds, while 0.1% HCOOH is added to the water.
- The preparative high pressure chromatography (HPLC) on normal phase of the example compounds according to the invention is carried out with columns made by Macherey & Nagel (name: Nucleosil, 50-7, 40×250 mm) and VDSoptilab (name: Kromasil 100 NH2, 10 μM, 50×250 mm). Different gradients of DCM/MeOH are used to elute the compounds, while 0.1% NH3 is added to the MeOH.
- The analytical HPLC (reaction control) of intermediate compounds is carried out using columns made by Agilent (names: Zorbax SB-C8, 5 μm, 21.2×50 mm or Zorbax SB-C8 3.5 μm 2.1×50 mm) and Phenomenex (name: Gemini C18 3 μm 2×30 mm). The analytical equipment is also equipped with a mass detector in each case.
- HPLC-Mass Spectroscopy/UV-Spectrometry
- The retention times/MS-ESI+ for characterising the example compounds according to the invention are produced using different HPLC-MS apparatus (high performance liquid chromatography with mass detector). Compounds that elute at the injection peak are given the retention time tRet=0.00.
- Details of the methods:
-
- HPLC: Agilent 1100 Series
- MS: Agilent LC/MSD SL
- Column: Waters, Xterra MS C18, 2.5 μm, 2.1×30 mm, Part. No. 186000592
- Eluant: A: H2O with 0.1% HCOOH; B: acetonitrile (HPLC grade)
- Detection: MS: Positive and negative mode
- Mass range: 120-900 m/z
- Flow 1.10 mL/min
- Column temp.: 40° C.
- Gradient: 0.00 min: 5% eluant B
- 0.00-2.50 min: 5%→95% eluant B
- 2.50-2.80 min: 95% eluant B
- 2.81-3.10 min: 95%→5% eluant B
HPLC-MS method 2 - HPLC: HP 1100
- MS: Waters ZQ2000
- Column: Waters, Sunfire C18, 3.5 μm, 4.6×50 mm
- Eluant: A: H2O with 0.1% TFA; B: acetonitrile with 0.1% TFA (in each case HPLC grade)
- Detection: MS: positive mode
- Mass range: 120-820 m/z
- Flow 1.5 mL/min
- Column temp.: 40° C.
- Gradient: 0.00 min: 5% eluant B
- 0.00-2.00 min: 5%→100% eluant B
- 2.00-2.50 min: 100% eluant B
- 2.50-2.60 min: 100%→5% eluant B
-
- HPLC: HP 1100
- MS: Waters ZQ2000
- Column: Supelco, Ascentis C18, 2.7 μm, 4.6×50 mm
- Eluant: A: H2O with 0.1% TFA; B: acetonitrile with 0.1% TFA (in each case HPLC grade)
- Detection: MS: Positive mode
- Mass range: 120-820 m/z
- Flow 1.5 mL/min
- Column temp.: 40° C.
- Gradient: 0.00 min: 5% eluant B
- 0.00-2.00 min: 5%→100% eluant B
- 2.00-2.50 min: 100% eluant B
- 2.50-2.60 min: 100%→5% eluant B
- The compounds according to the invention are prepared by the methods of synthesis described hereinafter, in which the substituents of the general formulae have the meanings given hereinbefore. These methods are intended as an illustration of the invention, without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or may be prepared analogously to known compounds or methods described herein. Substances described in the literature are prepared according to the published methods of synthesis.
- Trisubstituted pyrimidopyrimidines I may be obtained for example by two alternative methods according to Reaction scheme A (synthesis route 1 or 2).
- Starting from 2,4,8-trichloro-pyrimido[5,4-d]pyrimidine P-1a the chlorine atoms are successively substituted. In the first step the substitution is carried out using ammonia in the 4-position. In the second step the 8-position of the intermediate products P-2a is substituted by the aniline components A-1 or A-2, preferably under basically catalysed conditions at elevated temperature.
- If A-1 is used the complete left-hand molecular part of the end compounds I is thereby introduced into the intermediate compound Z-2, so that finally there only remains the substitution in the 2-position by components R1—H (E-3), which are preferably primary and secondary (also cyclic) amines and alcohols (in the form of the alkoxides). The components A-1 are obtained by amide coupling of the nitrocarboxylic acids E-1 with amines E-2 to form the intermediate product Z-1 and subsequent reduction of the nitro group. To carry out the amide coupling common coupling reagents as used in peptide chemistry (e.g. HATU or TBTU), are optionally used or the nitro acids E-1 are activated in some other way, e.g. as acid halides (e.g. with thionyl chloride, oxalyl chloride, GHOSEZ reagent).
- By contrast, by using A-2 first of all only the central phenyl or heteroaryl ring and a protected linker fragment (carboxylate) of the later linker L2 (e.g. amide) is incorporated, before the group R1 is introduced analogously. Therefore in this case additional reaction steps (saponification, activation, amidation) are needed to obtain compounds I. The amide coupling is carried out as described hereinbefore for the nitro acids E-1.
- Alternatively to P-1a other educts P-1 are possible which allow successive and selective substitution, i.e. have other leaving groups.
- Both the group R1 and the group R2 of compounds I according to the invention may be modified in other reaction steps (not shown), to obtain other compounds I according to the invention. These reaction steps may be reactions of substitution, alkylation, acylation or addition.
-
- 2,4,8-trihydroxy-pyrimido[5,4-d]pyrimidine (40 g, 222 mmol), potassium chloride (1.68 g, 22.53 mmol) and phosphorus pentachloride (152 g, 730 mmol) are placed in phosphorus oxychloride (240 mL). The reaction mixture is refluxed for 5 h. After cooling the mixture is evaporated down, the residue is triturated several times with petroleum ether and decanted off. The precipitate remaining is mixed with ice water, suction filtered, dissolved in DCM, dried on sodium sulphate and filtered off. The mother liquor is mixed with activated charcoal and heated. The activated charcoal is suction filtered, the filtrate is filtered through silica gel, washed with DCM, evaporated down using the rotary evaporator and 2,4,8-trichloro-pyrimido[5,4-d]pyrimidine P-1a (HPLC-MS: MS (M+H)+=234/236/238/240) is obtained. P-1a is used further without any further purification (purity approx. 95%).
-
- P-1a (95%; 4.0 g, 16.14 mmol) is placed in THF (350 mL) and TEA (2.26 mL, 16.14 mmol). The reaction mixture is cooled to approx. −65° C. with a bath of acetone and dry ice. Then ammonia (0.5 M in dioxane; 41.96 mL, 20.98 mmol) is slowly added dropwise. The reaction mixture is stirred further and slowly heated to RT. After 16 h the reaction mixture is evaporated down, the residue is taken up in 300 mL EE and extracted with 1×200 mL and 2×100 mL water. The organic phase is dried on MgSO4, filtered and evaporated down using the rotary evaporator. The intermediate product P-2a (HPLC-MS: tRet.=0.92 min; MS (M+H)+=216/218) is further reacted directly.
-
- 4-methyl-3-nitrobenzoic acid E-1a (2.0 g, 11 mmol) is taken up in DCM (40 mL) and mixed with TEA (5.1 mL, 27.6 mmol) and TBTU (3.9 g, 12.2 mmol). After 10 min 4-methoxy-3-trifluoromethylaniline E-2a (2.11 g, 11 mmol) is added and the mixture is stirred for another 2 h at RT. The precipitate formed is filtered off, washed repeatedly with water, dried and Z-1a (MS (M+H)+=355) is obtained.
- The aromatic nitro compound Z-1a (3.5 g, 9.9 mmol) is taken up in EtOH (30 mL), mixed with an ammonium chloride solution (264 mg, 4.94 mmol in 20 mL H2O) and heated to 70° C. At this temperature iron powder (5.52 g, 99 mmol) is added batchwise and the mixture is stirred for a further 4 h at 70° C. After cooling it is filtered through silica gel, washed with DCM/MeOH, the filtrate obtained is dried using the rotary evaporator and A-1a is obtained.
-
- E-1a (2.0 g, 11.04 mmol) is taken up in DCM (40 mL) and mixed with TEA (5.1 mL, 27.6 mmol) and HATU (6.3 g, 16.6 mmol). After 10 min aniline E-2b (3.41 g, 11.04 mmol) is added and the mixture is stirred for another 2 h at RT. For working up it is diluted with water and the phases are separated. The organic phase is extracted 1× with saturated NH4Cl solution, 1× with saturated NaHCO3 solution and 1× with saturated NaCl solution, dried on MgSO4, filtered, evaporated down using the rotary evaporator and Z-1b is obtained.
- The aromatic nitro compound Z-1b (3.5 g, 8.04 mmol) is taken up in EtOH (30 mL), combined with an ammonium chloride solution (215 mg, 4.02 mmol in 20 mL H2O) and heated to 70° C. At this temperature iron powder (4.49 g, 80.4 mmol) is added batchwise and the mixture is stirred for a further 5 h at 70° C. After cooling it is filtered through silica gel, washed with DCM/MeOH (9:1), the filtrate obtained is dried using the rotary evaporator and A-1b is obtained.
- Analogously to the method for synthesising A-1a and A-1b further anilines A-1 may be obtained from the corresponding educts E-1 and E-2.
-
- P-2a (200 mg, 0.93 mmol), aniline A-1a (300 mg, 0.93 mmol) and TEA (155 μL, 1.53 mmol) are placed in DMF (3 mL). The reaction mixture is stirred overnight at 65° C. The reaction mixture is combined with 20 mL water and stirred for 15 min. The precipitate formed is filtered off, washed with diethyl ether, taken up in toluene, evaporated down and Z-2a is obtained.
-
- P-2a (200 mg, 0.93 mmol) and aniline A-1c (291 mg, 0.93 mmol) are taken up in dioxane (3 mL). Hydrogen chloride (1M in Et2O, 5 μL, 0.102 mmol) is added. The reaction mixture is stirred for 25 min at 65° C. in the microwave reactor. The precipitate formed is filtered off, washed with water, taken up in toluene, evaporated down and Z-2b is obtained.
- Analogously to the methods for synthesising Z-2a and Z-2b further intermediate compounds Z-2 are obtained by reacting components A-1 with P-2a.
-
- Z-2a (50 mg, 0.1 mmol) and N-methylpiperazine E-3a (40 mg, 0.4 mmol) are taken up in 0.5 mL DMSO and DIPEA (180 μL, 1.4 mmol) is added. The reaction mixture is stirred for 25 min at 120° C. in the microwave reactor. The reaction mixture is filtered and purified by preparative HPLC. The product-containing fractions of I-1 (HPLC-MS: tRet.=2.17 min; MS (M+H)+=568) are freeze-dried.
-
- P-2a (1.439 g, 6.6 mmol) and aniline A-2a (1.0 g, 6.05 mmol) are placed in THF (5 mL). The reaction mixture is stirred overnight at RT. The precipitate formed is filtered off, dried and Z-3a is obtained.
- Analogously to the method for synthesising Z-3a further intermediate compounds Z-3 are obtained by reacting components A-2 with P-2a.
-
- Ester Z-3a (1.3 g, 3.77 mmol) is taken up in 25 mL DMSO with DIPEA (2.979 mL, 17.4 mmol) and N-methylpiperazine E-3a (0.443 mL, 4.351 mmol) is added. The reaction mixture is stirred for 20 min at 120° C. in the microwave reactor. The reaction mixture is mixed with water, the precipitate formed is filtered off, taken up in toluene, evaporated down 2× azeotropically and Z-4a is obtained.
- Analogously to the method for synthesising Z-4-a further intermediate compounds Z-4 are obtained by reacting intermediate compounds Z-3 with components E-3.
-
- Methylester Z-4-a (1.216 g, 2.98 mmol) is placed in MeOH (30 mL) and mixed at RT with an aqueous NaOH solution (5.0 mol/L, 12.146 mL, 60.73 mmol). Then the mixture is stirred overnight at 50° C. For working up the pH is adjusted to neutral by the addition of an HCl solution. The reaction mixture is extracted 2× with water/EE (1:1), the organic phases are dried on MgSO4, filtered, evaporated down and Z-5a is obtained.
- Benzoic acid Z-5a (100 mg, 0.25 mmol) is taken up in DCM (5 mL) and mixed under argon with thionyl chloride (300 μL, 2.38 mmol). The reaction mixture is stirred for 1 h at RT. Then the mixture is evaporated down, dried azeotropically with dry toluene and Z-6a is obtained.
- Acid chloride Z-6a (100 mg, 0.24 mmol) is taken up in DCM (3 mL) and mixed with 3-bromo-5-trifluoromethyl-phenylamine E-2c (58 mg, 0.24 mmol) and pyridine (100 μL). The reaction mixture is stirred for 2 h at RT. For working up the mixture is evaporated down, taken up in DMSO, filtered and purified by preparative HPLC. The product-containing fractions of I-2 (HPLC-MS: tRet.=2.44 min; MS (M+H)+=616/618) are freeze-dried.
- Analogously to methods a) to g) (synthesis route 1) or a), b) and h) to j) (synthesis route 2) besides I-1 and I-2 the following compounds I-3 to I-88 according to the invention are also prepared (Table 1).
-
TABLE 1 tRet. (HPLC) MS # Structure [min] (M + H)+ I-1 2.17 568 I-2 2.44 616/618 I-3 1.70 552 I-4 1.68 524 I-5 1.67 538 I-6 1.67 526 I-7 1.47 621 I-8 1.51 635 I-9 2.14 517 I-10 2.16 600 I-11 2.22 531 I-12 1.94 599 I-13 1.88 613 I-14 1.98 530 I-15 2.18 651 I-16 2.36 665 I-17 2.23 582 I-18 1.91 516 I-19 2.11 524 I-20 2.23 538 I-21 2.27 607 I-22 2.29 621 I-23 2.31 558 I-24 2.38 572 I-25 2.44 641 I-26 2.41 602/604 I-27 2.51 616/618 I-28 2.44 685/687 I-29 2.75 699/701 I-30 2.28 554 I-31 2.31 568 I-32 2.35 637 I-33 2.45 651 I-34 2.04 542 I-35 1.93 530 I-36 1.89 528 I-37 2.38 558 I-38 2.06 586 I-39 2.23 570 I-40 2.10 613 I-41 1.98 560 I-42 2.16 542 I-43 2.12 556 I-44 2.26 613 I-45 2.15 615 I-46 2.46 544 I-47 2.51 584 I-48 2.30 544 I-49 2.29 586 I-50 2.48 614 I-51 2.42 570 I-52 2.18 599 I-53 2.48 556 I-54 2.28 568 I-55 1.67 538 I-56 1.45 621 I-57 1.76 592 I-58 1.73 578 I-59 1.69 538 I-60 1.46 615 I-61 0.0 635 I-62 1.70 552 I-63 2.47 616 I-64 1.71 566 I-65 1.66 550 I-66 1.66 524 I-67 1.82 615 I-68 1.70 552 I-69 1.78 514 I-70 2.38 639 I-71 2.23 563 I-72 1.98 530 I-73 2.17 539 I-74 2.36 572 I-75 2.15 618 I-76 2.32 625 I-77 2.32 637 I-78 2.43 583 I-79 2.44 595 I-80 2.31 526 I-81 2.39 652 I-82 2.23 520 I-83 2.66 562 I-84 2.47 572 I-85 2.11 556 I-86 2.42 627 I-87 2.56 621 I-88 2.42 639 - Example compounds II differ from those of type I by an inverted amide bond between the central (hetero-)aromatic six-membered ring and the group R2 (Reaction scheme B). These compounds are obtained analogously to the compounds I in terms of the method used, except that the reactivities are inverted accordingly in the educt components E-4 and E-5 or A-4 (compared with E-1 and E-2 or A-2).
- For compounds of type II for example the following two synthesis routes are possible: Starting from P-2a the 8-position is substituted by the aniline components A-3 or A-4. With regard to the use of A-3 reference is made to the remarks relating to Reaction scheme
- A (synthesis route 1 via intermediate compound Z-2). The components A-3 are obtained by amide coupling of the nitroanilines E-4 with carboxylic acids E-5 to obtain intermediate product Z-7 and subsequent reduction of the nitro group.
- When A-4 is used first of all only the central phenyl or heteroaryl ring and the precursor of a linker fragment (nitro→amino) of the later linker L2 is incorporated before the group R1 is introduced analogously. In this case additional reaction steps are necessary (reduction, activation, amidation) in order to obtain compounds II.
- Both the group R1 and the group R2 of compounds II according to the invention may be modified in other reaction steps (not shown), to obtain further compounds II according to the invention. These reaction steps may be reactions of substitution, alkylation, acylation or addition.
-
- 3-trifluoromethylbenzoic acid E-5a (10.03 g, 51.7 mmol) is taken up in 150 mL toluene. a solution of oxalyl chloride (7.6 mL, 57.58 mmol) in 100 mL toluene is added dropwise. DMF (4 mL) is added and the reaction mixture is stirred for 2 h at 90° C. Then it is evaporated down, the residue is taken up in 100 mL DCM and cooled with an ice bath. 4-Methyl-3-nitroaniline E-4-a (8.91 g, 56.8 mmol) and TEA (8.7 mL, 62.14 mmol) are added, the ice bath is removed and the reaction mixture is stirred overnight at RT. For working up it is filtered, washed with DCM and the filtrate is evaporated down. The residue is mixed with 0.5 M NaOH solution (20 mL), the precipitate formed is filtered off and washed with water. The solid is suspended in 20 mL 0.5 M HCl solution and 10 mL EE, stirred for 15 min at RT and filtered off. The solid is suspended in 30 mL TBME, stirred for 10 min in the ultrasound bath, filtered off, dried and Z-7a (HPLC-MS: tRet.=2.30 min; MS (M+H)+=325) is obtained.
- The aromatic nitro compound Z-7a (4.4 g, 13.57 mmol) is taken up in THF (85 mL) and MeOH (15 mL). Pd/C (200 mg) is carefully added. The reaction vessel is filled with 7 bar H2, the reaction mixture is stirred overnight at RT, filtered through Celite, washed with THF, the filtrate obtained is dried using the rotary evaporator and A-3a (HPLC-MS: tRet.=1.73 min; MS (M+H)+=295) is obtained.
- Analogously to the method for synthesising A-3a further anilines A-3 were obtained from the corresponding educts E-4 and E-5.
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- P-2a (975 mg, 4.51 mmol) is taken up in DMF (25 mL) and TEA (754 μL, 5.41 mmol) is added. The reaction mixture is combined with aniline A-3a (1.327 g, 4.51 mmol) and stirred overnight at RT. For working up 100 mL ice water are added, the precipitate formed is filtered off and Z-8a is obtained.
- Analogously to the method for synthesising Z-8a further intermediate compounds Z-8 are obtained by reacting components A-3 with P-2a.
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- Z-8a (50 mg, 0.11 mmol) is taken up in DMSO (900 μL), mixed with N-methylpiperazine E-3a (32 mg, 0.32 mmol) and stirred for 15 min at 150° C. in the microwave reactor. The reaction mixture is purified by preparative HPLC. The product-containing fractions of II-1 (HPLC-MS: tRet.=1.59 min; MS (M+H)+=538) are freeze-dried.
- Analogously to methods a) to c) (synthesis route 1) or synthesis route 2 described, in addition to II-1 the following compounds II-2 to II-19 according to the invention are also prepared (Table 2).
-
TABLE 2 tRet. (HPLC) MS # Structure [min] (M + H)+ II-1 1.59 538 II-2 1.63 552 II-3 1.73 553 II-4 1.66 546 II-5 1.80 546 II-6 1.80 546 II-7 2.29 483 II-8 1.42 621 II-9 1.75 592 II-10 1.69 578 II-11 1.64 538 II-12 1.74 615 II-13 1.68 552 II-14 0.0 635 II-15 1.64 552 II-16 2.40 616 II-17 1.68 566 II-18 1.61 550 II-19 1.62 524 - 2,8-disubstituted pyrimidopyrimidines III may also be obtained for example by the following methods (Reaction scheme C, synthesis routes 1-3).
- Starting from 8-chloro-2-methylsulphanyl-pyrimido[5,4-d]pyrimidine P-3a the 8-position is substituted by the aniline components A-1 or A-2, preferably under basically catalysed conditions at elevated temperature.
- If A-1 is used (synthesis route 1) the complete left-hand molecular part of the end compounds III is thereby introduced into the intermediate compound Z-12, so that finally there only remains the substitution in the 2-position by components R1—H (E-3), which are preferably primary and secondary (also cyclic) amines or alcohols (in the form of the alkoxides). For this, however, first the methylsulphanyl group has to be activated in the 2-position by oxidation to form the corresponding sulphoxide/sulphone for the substitution (for the synthesis of the components A-1 cf. the remarks made under Reaction scheme A). In this reaction, a mixture of the sulphoxide and sulphone is usually obtained, which is further reacted as one.
- By contrast, by using A-2 (synthesis routes 2 and 3) first of all only the central phenyl or heteroaryl ring and a protected linker fragment (carboxylate) of the later linker L2 (e.g. amide) is incorporated, before the group R1 is introduced. With the intermediate compound Z-14 there are the alternative possibilities of either oxidising/activating the methylsulphanyl group, then substituting it with a component E-3 and lastly, after saponification, introducing the group R2 (through the component E-2) (synthesis route 2) or first of all carrying out saponification and oxidation and then carrying out the nucleo-philic substitution by E-3 followed by the amide coupling of E-2 (synthesis route 3).
- Alternatively to P-3a other educts P-3 are possible which allow successive and selective substitution, i.e. have other leaving groups.
- Both the group R1 and the group R2 of compounds III according to the invention may be modified in other reaction steps (not shown), to obtain other compounds III according to the invention. These reaction steps may be reactions of substitution, alkylation, acylation or addition.
-
- 8-hydroxy-2-methylsulphanyl-pyrimido[5,4-d]pyrimidine (16.5 g, 85 mmol) is placed in acetonitrile (125 mL), combined with DMF (400 μL) and heated to 30° C. At this temperature the thionyl chloride (16 mL, 215 mmol) is added dropwise. The reaction mixture is stirred for 4.5 h at 95° C. After cooling it is evaporated down, the residue is taken up in DCM and filtered through silica gel. The filtrate is washed with a saturated NaHCO3 solution, dried on Na2SO4, filtered off, the solvent removed and P-3a (HPLC-MS: tRet.=1.64 min; MS (M+H)+=213/215) is obtained.
-
- Aniline A-1a (453 mg, 1.4 mmol) and 8-chloro-2-methylsulphanyl-pyrimido[5,4-d]pyrimidine P-3a (270 mg, 1.27 mmol) are placed in dioxane (3 mL) and DIPEA (352 μL, 1.9 mmol) and refluxed overnight. For working up the reaction mixture is evaporated down, the residue is suspended in MeOH, the precipitate formed is filtered off, dried and Z-12a (HPLC-MS: tRet.=1.99 min; MS (M+H)+=501) is obtained.
-
- Aniline A-1b (3.3 g, 8.14 mmol) and 8-chloro-2-methylsulphanyl-pyrimido[5,4-d]pyrimidine P-3a (1.73 g, 8.14 mmol) are placed in acetic acid (20 mL) and stirred overnight at 50° C. For working up the reaction mixture is evaporated down, the residue is suspended in isopropanol/water (1:1), the precipitate formed is filtered off, dried and Z-12b is obtained.
- Analogously to the methods for synthesising Z-12a and Z-12b further intermediate compounds Z-12 are obtained by reacting components A-1 with P-3a.
-
- Z-12a (310 mg, 0.62 mmol) is taken up in DCM (5 mL). Then at RT mCPBA (70%, 183 mg, 0.74 mmol) is added and the reaction mixture is stirred for 1 h at RT. The precipitate formed is filtered off, washed with DCM, dried and Z-13a is obtained. Sulphoxide/sulphone Z-13a (90 mg, 0.174 mmol) and N-methylpiperazine E-3a (31 μL, 0.28 mmol) are placed in dioxane (0.5 mL). TEA (51 μL, 0.35 mmol) is added dropwise. The reaction mixture is stirred for 2 h at 60° C. For working up the mixture is evaporated down, the residue is suspended in isopropanol/water and filtered off. The solid is washed with water, dissolved in acetonitrile/water/2 M HCl solution, freeze-dried and III-1 (HPLC-MS: tRet.=2.18 min; MS (M+H)+=553) is obtained.
-
- Methyl 3-amino-4-methylbenzoate A-2a (4.04 g, 24.45 mmol) and 8-chloro-2-methylsulphanyl-pyrimido[5,4-c/]pyrimidine P-3a (80%, 5.0 g, 18.81 mmol) are placed in dioxane (8 mL) and DIPEA (4.525 mL, 24.45 mmol) and refluxed overnight with stirring. For working up the reaction mixture is evaporated down, the residue is suspended in MeOH, the precipitate formed is filtered off, dried and Z-14a (HPLC-MS: tRet.=2.01 min; MS (M+H)+=342) is obtained.
- Analogously to the method for synthesising Z-14a further intermediate compounds Z-14 are obtained by reacting components A-2 with P-3a.
-
- Z-14a (5.5 g, 16.1 mmol) is taken up in DCM (40 mL), combined at RT with mCPBA (70%, 3.61 g, 16.1 mmol) and stirred for 1 h. The precipitate formed is filtered off, washed with DCM, dried and Z-15a (HPLC-MS: tRet.=1.45 min; MS (M+H(+Na))+=358(380)) is obtained.
- Sulphoxide/sulphone Z-15a (1.0 g, 2.8 mmol) and morpholine E-3b (704 μL, 7.28 mmol) are placed in dioxane (30 mL). TEA (815 μL, 5.6 mmol) is added dropwise to this suspension and then it is heated to 60° C. for 2 h. For working up the mixture is evaporated down, the residue is suspended with iPrOH/water, filtered, dried and Z-16a (HPLC-MS: tRet.=1.94 min; MS (M+H)+=381) is obtained.
-
- Z-14a (5.5 g, 16.1 mmol) is taken up in DCM (40 mL), combined at RT with mCPBA (70%, 3.61 g, 16.1 mmol) and stirred for 1 h. The precipitate formed is filtered off, washed with DCM, dried and Z-15a (HPLC-MS: tRet.=1.45 min; MS (M+H(+Na))+=358(380)) is obtained.
- Sulphoxide/sulphone Z-15a (3.0 g, 8.4 mmol) and 1-(2-methoxyethyl)-piperazine E-3c (2.5 mL, 16.8 mmol) are placed in dioxane (25 mL). TEA (3 mL, 23 mmol) is added dropwise to this suspension and then the mixture is heated to 60° C. for 2 h. For working up the mixture is evaporated down, the residue is suspended with iPrOH/water, filtered, dried and Z-16b (HPLC-MS: tRet.=1.95 min; MS (M+H)+=438) is obtained.
- Analogously to the methods for synthesising Z-16a and Z-16b other intermediate compounds Z-16 are obtained by oxidising components Z-14 and reacting with amines E-3. Further intermediate compounds Z-16 are obtained by reacting with alcohols E-3 (in the form of their alkoxides), e.g. with sodium methoxide.
-
- Z-16a (1.0 g, 2.63 mmol) is placed in THF (15 mL) and combined at RT with an aqueous LiOH solution (1 M, 10.5 mL). Then the mixture is refluxed for 2 h with stirring. For working up the pH is adjusted to 5.5 by the addition of a 1N HCl solution. After evaporation in vacuo the precipitate formed is filtered off, washed with water, dried and Z-17a (HPLC-MS: tRet.=1.31 min; MS (M+H)+=367) is obtained.
- Benzoic acid Z-17a (1.1 g, 3.0 mmol) is suspended in thionyl chloride and stirred for 1 h at 60° C. The reaction mixture is evaporated down and dried azeotropically with dry toluene. The acid chloride Z-18a (400 mg, 1.04 mmol) is then taken up in a little NMP (1.2 mL) and combined with 4-methoxy-3-trifluoromethyl-phenylamine E-2a (188 mg, 1.55 mmol) and DIPEA (300 μL, 1.75 mmol). For working up water is added, the precipitate obtained is filtered off, dried and Example compound III-2 (HPLC-MS: tRet.=2.20 min; MS (M+H)+=540) is obtained.
-
- Z-16b (3.42 g, 7.81 mmol) is placed in THF (25 mL) and combined at RT with an aqueous LiOH solution (1.3 g, 31.4 mmol in 10 mL). Then the mixture is refluxed for 2 h with stirring. For working up the pH is adjusted to 5.5 by the addition of a 1N HCl solution. After evaporation in vacuo the precipitate formed is filtered off, washed with 5 mL water, dried and Z-17b (HPLC-MS: tRet.=1.05 min; MS (M+H)+=424) is obtained.
-
- Z-14a (880 mg, 2.58 mmol) is placed in THF (30 mL) and 1M NaOH solution (3.87 mL, 3.87 mmol) is added. The reaction mixture is stirred for 3 h at 50° C. and then overnight at RT. For working up it is concentrated by rotary evaporation, the residue is acidified slightly with dilute HCl solution, the precipitate formed is suction filtered and washed with water. The intermediate product Z-19a (HPLC-MS: tRet.=0.83 min; MS (M+H)+=328) is triturated with a little EtOH, suction filtered and dried.
- Benzoic acid Z-19a (29.0 g, 88.59 mmol) is placed in glacial acetic acid (800 mL) and sodium periodate (19.139 g, 88.59 mmol) is added. The reaction mixture is heated for 3 h to 80° C. After cooling it is mixed with aqueous Na2S2O5 solution (15 mL; 10%) and largely concentrated by rotary evaporation. The residue is mixed with water, the precipitate formed is suction filtered, washed with water, dried in the vacuum dryer at 70° C. and Z-20a (HPLC-MS: tRet.=1.81 min; MS (M+H)+=360) is obtained.
- Analogously to the method for synthesising Z-20a further intermediate compounds Z-20 are obtained by saponification of components Z-14 and oxidation.
-
- Sulphoxide/sulphone Z-20a (2.0 g, 5.57 mmol), amine E-3d (1.137 g, 11.13 mmol) and DIPEA (1.94 mL, 11.03 mmol) are taken up in DMF (30 mL) and stirred overnight at RT. The solvent is spun off, the residue is mixed with a little water. The precipitate formed is suction filtered, washed with a little cold water, dried and Z-17a (HPLC-MS: tRet.=1.47 min; MS (M+H)+=382) is obtained.
- Benzoic acid Z-17a (50 mg, 0.13 mmol) is suspended in DCM (5 mL). 1-Chloro-N,N,2-trimethylpropenylamine (41 mg, 0.30 mmol) is added and the reaction mixture is stirred for 3 h at RT. Then it is concentrated by rotary evaporation and the residue is suspended in dioxane/acetonitrile (3 mL, 1:1). Benzylamine E-2c (100 mg, 0.50 mmol) and DIPEA (65 mg, 0.50 mmol) are added and the reaction mixture is stirred overnight at RT. For working up the mixture is concentrated by rotary evaporation, the residue is taken up in DMF and the reaction mixture is purified by RP-LC/MS. The product-containing fractions of III-3 (HPLC-MS: tRet.=1.91 min; MS (M+H)+=525) are freeze-dried.
- Analogously to the methods a) to d) (synthesis route 1) or a), e) to h) (synthesis route 2) as well as a), d), i) and k) (synthesis route 3), besides III-1, III-2 and III-3 the following compounds III-4 to III-608 according to the invention are also prepared (Table 3).
-
TABLE 3 tRet. (HPLC) # Structure [min] MS (M + H)+ III-1 2.18 553 III-2 2.21 540 III-3 1.91 527 III-4 2.27 562 III-5 1.74 575 III-6 2.56 572 III-7 1.73 587 III-8 1.75 601 III-9 1.73 573 III-10 2.46 558 III-11 1.72 617 III-12 2.26 560 III-13 2.41 544 III-14 1.69 561 III-15 1.73 603 III-16 2.27 518 III-17 2.08 558 III-18 1.65 571 III-19 2.33 568 III-20 1.64 583 III-21 1.77 597 III-22 1.64 569 III-23 2.35 554 III-24 1.63 613 III-25 2.29 556 III-26 2.09 540 III-27 2.34 557 III-28 1.63 599 III-29 2.74 514 III-30 2.07 546 III-31 2.32 559 III-32 2.32 556 III-33 2.33 585 III-34 1.65 557 III-35 2.82 542 III-36 1.64 601 III-37 2.69 544 III-38 2.16 528 III-39 2.27 545 III-40 1.64 587 III-41 2.80 502 III-42 2.29 596 III-43 2.41 609 III-44 2.57 606 III-45 2.41 621 III-46 1.78 635 III-47 2.44 607 III-48 2.72 592 III-49 2.40 651 III-50 2.24 594 III-51 2.38 578 III-52 1.70 595 III-53 2.46 637 III-54 2.30 552 III-55 2.29 545 III-56 1.73 558 III-57 2.61 555 III-58 1.72 570 III-59 2.56 584 III-60 1.70 556 III-61 2.51 541 III-62 1.70 600 III-63 2.26 543 III-64 2.43 527 III-65 2.53 544 III-66 1.69 586 III-67 2.57 511 III-68 2.92 521 III-69 2.59 467 III-70 1.57 536 III-71 1.62 550 III-72 1.53 522 III-73 2.25 507 III-74 1.54 566 III-75 1.99 509 III-76 1.99 493 III-77 1.52 510 III-78 1.53 552 III-79 1.94 524 III-80 1.81 507 III-81 1.80 505 III-82 1.89 489 III-83 1.82 463 III-84 2.37 495 III-85 2.66 505 III-86 1.84 520 III-87 2.08 517 III-88 2.50 491 III-89 2.32 493 III-90 2.43 477 III-91 1.78 494 III-92 1.79 536 III-93 2.36 451 III-94 2.15 437 III-95 2.38 518 III-96 2.46 532 III-97 1.54 546 III-98 1.53 298 (M + 2H)2+ III-99 1.63 305 (M + 2H)2+ III-100 1.55 282 (M + 2H)2+ III-101 1.48 285 (M + 2H)2+ III-102 1.67 314 (M + 2H)2+ III-103 1.62 305 (M + 2H)2+ III-104 1.47 304 (M + 2H)2+ III-105 1.65 307 (M + 2H)2+ III-106 1.68 296 (M + 2H)2+ III-107 1.31 307 (M + 2H)2+ III-108 1.52 297 (M + 2H)2+ III-109 1.59 289 (M + 2H)2+ III-110 1.46 291 (M + 2H)2+ III-111 1.54 282 (M + 2H)2+ III-112 1.64 290 (M + 2H)2+ III-113 1.32 307 (M + 2H)2+ III-114 1.31 III-115 1.54 276 (M + 2H)2+ III-116 1.44 269 (M + 2H)2+ III-117 1.67 290 (M + 2H)2+ III-118 1.70 314 (M + 2H)2+ III-119 1.51 306 (M + 2H)2+ III-120 1.72 311 (M + 2H)2+ III-121 1.62 313 (M + 2H)2+ III-122 1.50 290 (M + 2H)2+ III-123 1.45 293 (M + 2H)2+ III-124 1.67 322 (M + 2H)2+ III-125 1.60 313 (M + 2H)2+ III-126 1.44 312 (M + 2H)2+ III-127 1.64 315 (M + 2H)2+ III-128 1.67 304 (M + 2H)2+ III-129 1.28 316 (M + 2H)2+ III-130 1.95 610 III-131 1.59 297 (M + 2H)2+ III-132 1.43 299 (M + 2H)2+ III-133 1.51 290 (M + 2H)2+ III-134 1.63 298 (M + 2H)2+ III-135 1.29 316 (M + 2H)2+ III-136 1.27 316 (M + 2H)2+ III-137 1.50 284 (M + 2H)2+ III-138 1.41 277 (M + 2H)2+ III-139 1.65 298 (M + 2H)2+ III-140 1.67 322 (M + 2H)2+ III-141 1.53 300 (M + 2H)2+ III-142 1.62 III-143 1.53 III-144 1.47 287 (M + 2H)2+ III-145 1.61 307 (M + 2H)2+ III-146 1.47 306 (M + 2H)2+ III-147 1.64 309 (M + 2H)2+ III-148 1.31 309 (M + 2H)2+ III-149 1.50 299 (M + 2H)2+ III-150 1.59 291 (M + 2H)2+ III-151 1.46 293 (M + 2H)2+ III-152 1.53 III-153 1.63 292 (M + 2H)2+ III-154 1.32 309 (M + 2H)2+ III-155 1.52 278 (M + 2H)2+ III-156 1.44 III-157 1.67 292 (M + 2H)2+ III-158 1.76 311 (M + 2H)2+ III-159 1.65 313 (M + 2H)2+ III-160 1.55 290 (M + 2H)2+ III-161 1.41 321 (M + 2H)2+ III-162 1.51 293 (M + 2H)2+ III-163 1.70 322 (M + 2H)2+ III-164 1.64 313 (M + 2H)2+ III-165 1.50 312 (M + 2H)2+ III-166 1.67 315 (M + 2H)2+ III-167 1.72 304 (M + 2H)2+ III-168 1.34 316 (M + 2H)2+ III-169 1.49 299 (M + 2H)2+ III-170 1.56 290 (M + 2H)2+ III-171 1.66 298 (M + 2H)2+ III-172 1.36 316 (M + 2H)2+ III-173 1.34 316 (M + 2H)2+ III-174 1.55 284 (M + 2H)2+ III-175 1.47 277 (M + 2H)2+ III-176 1.69 298 (M + 2H)2+ III-177 1.72 322 (M + 2H)2+ III-178 1.61 352 (M + 2H)2+ III-179 1.28 477 III-180 1.54 536 III-181 1.57 648 III-182 1.57 551 III-183 1.47 475 III-184 1.46 469 III-185 1.28 433 III-186 1.31 318 (M + 2H)2+ III-187 1.26 463 III-188 1.57 537 III-189 1.46 461 III-190 1.46 455 III-191 1.27 419 III-192 1.48 311 (M + 2H)2+ III-193 1.48 450 III-194 1.51 406 III-195 1.50 564 III-196 1.33 637 III-197 1.28 465 III-198 1.55 524 III-199 1.58 636 III-200 1.57 539 III-201 1.48 463 III-202 1.47 457 III-203 1.29 421 III-204 1.52 312 (M + 2H)2+ III-205 1.54 452 III-206 1.88 511 III-207 1.89 526 III-208 1.79 450 III-209 1.79 444 III-210 1.57 408 III-211 1.61 310 (M + 2H)2+ III-212 1.67 448 III-213 2.00 507 III-214 2.00 522 III-215 1.92 446 III-216 1.64 555 III-217 1.61 537 III-218 1.65 539 III-219 1.64 567 III-220 1.69 571 III-221 1.57 551 III-222 1.64 553 III-223 1.26 256 (M + 2H)2+ III-224 1.66 525 III-225 1.69 555 III-226 1.65 525 III-227 1.57 537 III-228 1.25 249 (M + 2H)2+ III-229 1.67 511 III-230 1.69 541 III-231 1.65 543 III-232 1.62 525 III-233 1.66 527 III-234 1.65 555 III-235 1.71 559 III-236 1.58 539 III-237 1.65 541 III-238 1.27 500 III-239 1.68 513 III-240 1.70 543 III-241 2.00 514 III-242 1.90 526 III-243 1.47 244 (M + 2H)2+ III-244 2.04 500 III-245 2.12 510 III-246 2.01 522 III-247 1.58 242 (M + 2H)2+ III-248 2.16 496 III-249 2.26 526 III-250 1.93 508 III-251 1.49 576 III-252 1.32 325 (M + 2H)2+ III-253 1.92 440 III-254 1.71 404 III-255 1.55 303 (M + 2H)2+ III-256 1.58 434 III-257 2.04 508 III-258 1.94 432 III-259 1.95 426 III-260 1.72 390 III-261 1.81 524 III-262 2.40 538 III-263 1.12 484 III-264 2.13 502 III-265 2.17 512 III-266 2.14 494 III-267 2.16 496 III-268 2.22 524 III-269 2.24 528 III-270 2.17 510 III-271 1.68 469 III-272 2.20 482 III-273 2.16 519 III-274 1.95 533 III-275 2.10 495 III-276 2.03 493 III-277 2.08 605 III-278 2.15 496 III-279 1.50 526 III-280 1.79 533 III-281 1.76 550 III-282 1.82 545 III-283 1.75 538 III-284 1.80 562 III-285 1.80 520 III-286 1.87 530 III-287 1.82 512 III-288 1.92 542 III-289 1.95 546 III-290 1.88 528 III-291 2.02 530 III-292 1.85 537 III-293 1.67 551 III-294 1.88 498 III-295 2.10 623 III-296 1.46 531 III-297 1.55 541 III-298 1.53 523 III-299 1.56 553 III-300 1.62 557 III-301 1.56 539 III-302 1.85 512 III-303 1.37 562 III-304 1.87 540 III-305 1.45 522 III-306 1.97 528 III-307 1.72 524 III-308 2.38 510 III-309 1.32 485 III-310 1.82 525 III-311 1.53 548 III-312 1.48 634 III-313 1.97 518 III-314 2.16 528 III-315 1.80 510 III-316 1.87 508 III-317 1.86 534 III-318 1.80 506 III-319 1.86 550 III-320 1.61 549 III-321 1.75 511 III-322 1.69 509 III-323 1.86 621 III-324 1.72 524 III-325 1.60 448 III-326 1.59 442 III-327 2.14 512/513 III-328 2.03 516 III-329 2.06 526 III-330 2.03 508 III-331 2.13 542 III-332 2.06 524 III-333 2.05 533 III-334 1.87 547 III-335 2.00 509 III-336 2.40 539 III-337 1.90 544 III-338 1.97 619 III-339 2.41 509 III-340 1.88 535 III-341 2.31 497 III-342 1.48 517 III-343 1.87 527 III-344 1.63 548 III-345 2.23 513 III-346 1.54 408 III-347 2.11 540 III-348 1.91 502 III-349 2.15 510 III-350 2.24 498 III-351 2.20 622 III-352 2.03 516 III-353 1.86 488 III-354 2.14 488 III-355 2.09 511 III-356 2.26 540 III-357 2.08 489 III-358 2.09 477 III-359 2.16 503 III-360 2.35 517 III-361 2.16 517 III-362 2.42 517 III-363 2.13 503 III-364 2.07 489 III-365 2.23 503 III-366 2.27 495 III-367 2.07 484 III-368 2.37 517 III-369 2.22 503 III-370 2.08 601 III-371 2.24 500 III-372 2.06 516 III-373 2.00 529 III-374 2.43 540/542 III-375 2.21 556/558 III-376 2.19 522 III-377 2.36 506 III-378 2.14 535 III-379 2.17 549 III-380 1.54 440 III-381 2.02 493 III-382 2.20 612 III-383 2.20 513 III-384 1.73 506 III-385 2.04 630 III-386 1.81 513 III-387 1.65 506 III-388 1.86 612 III-389 1.93 630 III-390 1.86 544 III-391 1.73 492 III-392 1.63 492 III-393 2.02 515 III-394 2.27 603 III-395 1.96 550 III-396 2.15 534 III-397 2.18 546 III-398 2.03 520 III-399 1.96 520 III-400 2.15 520 III-401 2.02 534 III-402 1.97 601 III-403 2.14 585 III-404 2.17 597 III-405 2.04 571 III-406 2.06 521 III-407 2.60 652 III-408 2.58 664 III-409 2.49 582 III-410 1.83 526 III-411 2.28 542 III-412 2.24 491 III-413 2.66 650 III-414 2.26 612 III-415 2.80 638 III-416 2.64 608 III-417 2.25 620 III-418 2.20 598 III-419 2.48 650 III-420 2.45 599 III-421 2.00 559 III-422 2.45 585 III-423 2.25 567 III-424 2.29 679 III-425 1.96 545 III-426 2.18 568 III-427 2.20 597 III-428 2.50 518 III-429 2.18 522 III-430 2.28 529 III-431 1.85 565 III-432 2.04 623 III-433 2.13 579 III-434 2.03 595 III-435 2.01 581 III-436 1.91 567 III-437 2.10 581 III-438 2.38 612 III-439 2.37 624 III-440 2.49 594 III-441 2.29 622 III-442 2.33 610 III-443 2.24 567 III-444 2.68 595 III-445 2.38 524 III-446 1.98 515 III-447 2.42 543 III-448 1.93 501 III-449 2.72 566 III-450 2.34 610 III-451 2.54 656 III-452 2.36 628 III-453 2.53 613 III-454 2.26 592 III-455 2.76 652 III-456 2.40 638 III-457 2.30 610 III-458 2.33 624 III-459 2.46 595 III-460 2.69 650 III-461 2.41 636 III-462 2.21 608 III-463 2.25 622 III-464 2.49 542 III-465 2.10 504 III-466 2.54 530 III-467 2.35 512 III-468 2.39 500 III-469 2.40 612 III-470 2.37 624 III-471 2.04 490 III-472 2.24 513 III-473 2.31 542 III-474 2.27 491 III-475 2.70 582 III-476 2.23 544 III-477 2.83 570 III-478 2.48 552 III-479 2.65 540 III-480 2.45 531 III-481 2.38 599 III-482 2.28 572 III-483 2.39 599 III-484 2.27 528 III-485 2.49 570 III-486 2.16 585 III-487 2.03 475 III-488 1.99 600 III-489 1.80 572 III-490 2.09 556 III-491 1.92 516 III-492 2.04 530 III-493 2.05 528 III-494 2.34 544 III-495 1.91 530 III-496 1.85 516 III-497 1.75 514 III-498 2.04 732 III-499 2.21 488 III-500 2.54 484 III-501 2.26 683 III-502 2.16 647 III-503 2.28 626 III-504 2.13 502 III-505 1.87 678 III-506 2.17 626 III-507 2.07 590 III-508 2.04 490 III-509 2.47 736 III-510 2.41 621 III-511 2.35 628 III-512 2.13 508 III-513 1.99 502 III-514 2.36 612 III-515 1.95 488 III-516 2.18 489 III-517 2.16 546 III-518 2.30 598 III-519 2.42 497 III-520 2.32 495 III-521 2.36 509 III-522 2.38 531 III-523 2.09 623 III-524 1.99 622 III-525 1.97 595 III-526 1.80 638 III-527 1.86 608 III-528 2.26 627/629 III-529 1.92 639 III-530 1.86 576 III-531 1.89 592 III-532 1.96 592 III-533 2.11 601/603 III-534 2.08 652 III-535 2.01 597 III-536 1.99 585 III-537 1.89 634 III-538 2.18 633 III-539 2.28 623 III-540 2.13 611 III-541 2.38 625 III-542 2.21 613 III-543 2.11 568 III-544 1.92 568 III-545 2.17 568 III-546 1.91 554 III-547 2.15 526 III-548 2.00 554 III-549 1.86 535 III-550 2.14 568 III-551 2.00 554 III-552 1.84 652 III-553 2.24 650 III-554 2.20 650 III-555 2.12 593 III-556 2.27 621 III-557 1.98 636 III-558 1.93 623 III-559 2.11 651 III-560 2.20 607 III-561 2.02 567 III-562 2.22 654 III-563 1.98 571 III-564 2.07 571 III-565* 1.88 447 III-566* 2.37 473 III-567* 2.31 581 III-568* 2.15 455 III-569* 2.11 485 III-570* 2.25 443 III-571* 2.19 555 III-572* 2.28 538 III-573* 2.59 595 III-574* 2.21 567 III-575* 1.85 433 III-576* 2.11 553 III-577* 2.07 434 III-578* 2.08 456 III-579* 2.24 485 III-580 2.21 503 III-581 2.08 503 III-582 2.10 560 III-583 2.23 505 III-584 2.20 554 III-585 2.12 554 III-586 2.12 611 III-587 2.29 556 III-588** 1.98 516 III-589** 2.01 530 III-590** 1.96 518 III-591** 2.02 503 III-592 1.81 571 III-593 1.83 622 III-594 1.94 560 III-595 1.66 526 III-596 2.01 585 III-597 2.05 595 III-598 1.93 504 III-599 2.17 595 III-600 2.18 569 III-601 2.14 604 III-602 1.86 571 III-603 2.04 542 III-604 2.10 580 III-605 1.66 483 III-606 2.00 568 III-607 2.15 642 III-608 2.23 629 *using NaOMe instead of amines (E-3) **using phenols instead of anilines A-1 - Example compounds IV differ from those of type III by an inverted amide bond between the central (hetero-)aromatic six-membered ring and the group R2 (Reaction scheme D). These compounds are obtained analogously to the compounds III in terms of the method used, except that the reactivities are inverted accordingly in the educt components E-4 and E-5 (for the synthesis of A-3, cf. Reaction scheme B) or A-4 (compared with E-1 and E-2 or A-2, cf. Reaction schemes A and C).
- For the compound of type IV for example the following two synthesis routes are possible:
- Starting from P-3a the 8-position is substituted by the aniline components A-3 or A-4, preferably under basically catalysed conditions at elevated temperature.
- With regard to the use of A-3 (synthesis route 1) reference is made to the remarks relating to Reaction scheme C (synthesis route 1 via intermediate compound Z-12) (final substitution by E-3 after oxidative activation of the methylsulphanyl group; regarding the synthesis of components A-3 cf. the remarks under Reaction scheme B).
- When A-4 is used (synthesis routes 2 and 3) first of all only the central phenyl or heteroaryl ring and the precursor of a linker fragment (nitro→amino) of the later linker L2 is incorporated. With the intermediate compound Z-24 there are the alternative possibilities of either oxidising/activating the methylsulphanyl group, then substituting it with a component E-3 and lastly, after reduction, introducing the group R2 (via the component E-5) (synthesis route 2) or first of all carrying out reduction and amide coupling with E-5 and then after oxidative activation carrying out the nucleophilic substitution by E-3 (synthesis route 3).
- Both the group R1 and the group R2 of compounds IV according to the invention may be modified in other reaction steps (not shown), to obtain further compounds IV according to the invention. These reaction steps may be reactions of substitution, alkylation, acylation or addition.
-
- 8-chloro-2-methylsulphanyl-pyrimido[5,4-d]pyrimidine P-3a (3 g, 14.11 mmol) and nitroaniline A-4-a (2.21 g, 14.53 mmol) are placed in dioxane (25 mL) and DIPEA (3.393 mL, 18.34 mmol) and refluxed overnight with stirring. For working up the reaction mixture is evaporated down, the residue is suspended in MeOH, the precipitate formed is filtered off, dried and Z-24a (HPLC-MS: tRet.=2.05 min; MS (M+H)+=329) is obtained.
- Analogously to the method for synthesising Z-24a further intermediate compounds Z-24 are obtained by reacting components A-4 with P-3a.
-
- Z-24a (5 g, 14.47 mmol) is taken up in DCM (50 mL), combined at RT with mCPBA (3.24 g, 14.47 mmol) and stirred for 2 h at RT. The reaction mixture is filtered off, the filtrate is diluted with DCM and washed 3× with saturated NaHCO3 solution. The organic phase is dried on Na2SO4, filtered off, evaporated down and Z-25a is obtained. Z-25a is further reacted directly without any further purification (content of sulphoxide/sulphone approx. 85%).
- Sulphoxide/sulphone Z-25a (85%, 1 g, 2.47 mmol) and N-methylpiperazine E-3a (4.381 mL, 3.95 mmol) are placed in dioxane (6 mL). TEA (718 μL, 4.94 mmol) is added dropwise to this suspension, then it is heated to 60° C. and stirred for 1 h. For working up the mixture is evaporated down, the residue is suspended with iPrOH/water, filtered and dried. The precipitate is purified by chromatography on NP with DCM/MeOH (9:1) and Z-26a (HPLC-MS: tRet.=1.96 min; MS (M+H)+=381) is obtained.
- Analogously to the method for synthesising Z-26a further intermediate compounds Z-26 are obtained by oxidation of components Z-24 and reaction with amines E-3. Further intermediate compounds Z-26 are obtained by reacting with alcohols E-3 (in the form of their alkoxides), e.g. with sodium methoxide.
-
- Nitro compound Z-26a (490 mg, 1.29 mmol) is taken up in EtOH (10 mL), combined with ammonium chloride (34 mg, 0.64 mmol) in water (10 mL) and heated to 60° C. At this temperature iron powder (719 mg, 12.88 mmol) is added batchwise and the mixture is stirred for a further 1.5 h at 60° C. After cooling it is filtered through silica gel, washed with DCM/MeOH, the filtrate obtained is dried using the rotary evaporator and Z-27a (HPLC-MS: tRet.=1.64 min; MS (M+H)+=351) is obtained.
- 4-methoxy-3-trifluoromethylbenzoic acid E-5b (62 mg, 0.29 mmol) is taken up in NMP (750 μL) and combined with DIPEA (166 μL, 1.03 mmol) and HATU (147 mg, 0.39 mmol). After 1 h aniline Z-27a (90 mg, 0.26 mmol) is added and the mixture is stirred at RT. The reaction mixture is purified by preparative HPLC and Example compound IV-1 (HPLC-MS: tRet.=2.17 min; MS (M+H)+=553) is obtained.
-
- Nitro compound Z-24a (2.96 g, 9.02 mmol) is taken up in dioxane (100 mL), combined with ammonium chloride (241 mg, 4.51 mmol) in water (100 mL) and heated to 70° C. At this temperature iron powder (5.04 g, 90.2 mmol) is added batchwise and the mixture is stirred for a further 5 h at 70° C. After cooling it is filtered through silica gel, washed with DCM/MeOH, the filtrate obtained is dried using the rotary evaporator and Z-28a (HPLC-MS: tRet.=1.70 min; MS (M+H)+=299) is obtained.
- Benzoic acid E-5c (1 g, 5.29 mmol) is taken up in NMP (10 mL) and combined with DIPEA (3.415 mL, 21.14 mmol) and HATU (3.02 g, 7.93 mmol). After 1 h aniline Z-28a (1.58 g, 5.29 mmol) is added and the mixture is stirred at RT. The reaction mixture is mixed with water. The precipitate formed is filtered off, washed repeatedly with water, then dried and Z-29a (HPLC-MS: tRet.=2.16 min; MS (M+H)+=470) is obtained.
- Analogously to the method for synthesising Z-29a further intermediate compounds Z-29 are obtained by reduction of components Z-24 and reaction with acids E-5.
-
- Z-29a (1.91 g, 4.07 mmol) is suspended in DCM (40 mL), combined at 0° C. with mCPBA (950 mg, 4.23 mmol) and stirred for 2 h at RT. The reaction mixture is diluted with DCM and washed 2× with saturated NaHCO3 solution. The organic phase is dried on Na2SO4, filtered off, evaporated down and Z-30a is obtained.
- Sulphoxide/sulphone Z-30a (1.39 g, 2.86 mmol) is placed in dioxane (10 mL) and mixed with TEA (1.607 mL, 11.45 mmol). Morpholine E-3b (250 μL, 2.86 mmol) is added dropwise to this suspension, it is heated to 60° C. and stirred for 4 h. For working up the mixture is evaporated down, the residue is dissolved with DMF, purified by preparative HPLC and Example compound IV-2 (HPLC-MS: tRet.=2.09 min; MS (M+H)+=509) is obtained.
- Analogously to methods a) to c) (synthesis route 2) or a), d) and e) (synthesis route 3) as well as synthesis route 1 shown, besides IV-1 and IV-2 the following compounds IV-3 to IV-68 according to the invention are also prepared (Table 4).
-
TABLE 4 tRet. (HPLC) # Structure [min] MS (M + H)+ IV-1 2.17 533 IV-2 2.09 509 IV-3 2.17 523 IV-4 1.99 501 IV-5 2.22 502 IV-6 2.40 541 IV-7 2.04 522 IV-8 2.24 553 IV-9 2.16 621 IV-10 2.13 515 IV-11 2.58 486 IV-12 2.19 467 IV-13 2.30 566 IV-14 2.30 460 IV-15 2.31 498 IV-16 2.51 543 IV-17 2.15 524 IV-18 2.24 623 IV-19 2.23 517 IV-20 2.25 555 IV-21 2.54 557 IV-22 2.16 538 IV-23 2.28 637 IV-24 2.27 531 IV-25 2.28 569 IV-26 2.29 548 IV-27 2.14 536 IV-28 2.05 536 IV-29 2.16 550 IV-30 1.98 509 IV-31 2.20 537 VI-32 1.99 509 IV-33 2.26 529 IV-34 2.18 511 IV-35 2.19 511 IV-36 1.93 550 IV-37 2.13 523 IV-38 2.03 523 IV-39 2.40 551 IV-40* 1.99 454 IV-41* 2.08 447 IV-42* 2.12 485 IV-43* 2.11 455 IV-44* 1.92 433 IV-45* 2.18 485 IV-46* 2.11 553 IV-47* 2.06 535 IV-48* 2.17 434 IV-49* 2.28 447 IV-50* 2.23 489 IV-51* 2.11 456 IV-52* 1.99 454 IV-53** 0.0 497 IV-54** 1.78 485 IV-55** 1.86 497 IV-56** 1.72 471 IV-57** 1.59 471 IV-58** 1.56 457 IV-59** 1.43 511 IV-60** 1.60 469 IV-61** 1.49 559 IV-62** 1.39 499 IV-63** 1.49 455 IV-64** 1.44 443 IV-65** 1.58 457 IV-66** 1.29 429 IV-67 1.96 621 IV-68 1.87 607 *using NaOMe instead of amines (E-3) **by coupling a sulphonic acid instead of carboxylic acid E-5 to the intermediate Z-27 - Compounds of type V and VI are pyrimidopyrimidines monosubstituted in the 8-position (Reaction scheme E).
- Starting from 4,8-dichloro-pyrimido[5,4-d]pyrimidine P-4-a, one chlorine atom is substituted nucleophilically by the aniline components A-1 (synthesis route 1), A-2 (synthesis route 2) or A-3 (synthesis route 3) while the other chlorine atom is reductively removed.
- The substitution by A-1 or A-2 to obtain the intermediate compounds Z-31 or Z-32 is carried out in comparable manner to the steps illustrated in Reaction scheme A or C (reactions to obtain intermediate compounds Z-2, Z-3, Z-12 or Z-14). Whereas example compounds V may be obtained directly from Z-31 (reduction), saponification and amide coupling with amines E-2 are also necessary in addition to the reduction for the synthesis starting from Z-32.
- By using the anilines A-3, after reduction of the intermediate compound Z-36, example compounds VI with an inverted amide bond are obtained (regarding the synthesis of A-1 or A-3 cf. the remarks made on Reaction scheme A or B)
-
- 4,8-dihydroxypyrimidopyrimidine (2.0 g, 12 mmol) is taken. Phosphorus oxychloride (7.0 mL, 76 mmol) and potassium chloride (2.6 g, 35 mmol) are added. Finally, phosphorus pentachloride (6.2 g, 30 mmol) is added batchwise. The reaction mixture is stirred for 1.5 d at 130° C. and 1.5 d at RT. The excess POCl3 is distilled off, the residue is mixed with water and extracted several times with DCM. The combined organic phases are mixed with MgSO4, filtered through silica gel and washed with DCM. The filtrate is slowly evaporated down to about 15 mL. The precipitate formed is suction filtered and P-4-a (HPLC-MS: MS (M+H)+=200/202/204) is obtained.
-
- 4,8-dichloropyrimidopyrimidine P-4-a (100 mg, 0.50 mmol) is placed in THF (2 mL) while cooling with ice. Aniline A-1d (195 mg, 0.50 mmol) and DIPEA (0.1 mL, 0.58 mmol) are added. The reaction mixture is thawed to RT overnight and stirred. For working up it is mixed with a little acetonitrile. The precipitate is filtered off, dried and Z-31a is obtained. Analogously to the method for synthesising Z-31a further intermediate compounds Z-31 are obtained by reacting components A-1 with P-4-a.
-
- 4,8-dichloropyrimidopyrimidine P-4-a (1.0 g, 4.98 mmol) is placed in THF (20 mL) and cooled in the ice bath. Aniline A-2a (840 mg, 4.98 mmol) is added batchwise. The reaction mixture is combined with DIPEA (940 μL, 5.49 mmol) and thawed to RT overnight and stirred. For working up the mixture is evaporated to dryness, taken up in acetonitrile and treated for 5 min in the ultrasound bath. The precipitate is filtered off, washed with a mixture of water and acetonitrile (1:1), dried and Z-32a (HPLC-MS: tRet.=1.83 min; MS (M+H)+=330) is obtained.
- Analogously to the method for synthesising Z-32a further intermediate compounds Z-32 are obtained by reacting components A-2 with P-4-a.
-
- Z-32a (1.25 g, 3.79 mmol) is suspended in MeOH (130 mL), combined with Raney nickel and hydrogenated overnight at 2 bar. The reaction mixture is filtered off from the catalyst, evaporated to dryness and Z-33a (HPLC-MS: tRet.=1.58 min; MS (M+H)+=296) is obtained, which is reacted further without any further working up (purity approx. 80%). Analogously to the method for synthesising Z-33a further intermediate compounds Z-33 are obtained by reduction of intermediate compounds Z-32.
- e) Method for Synthesising Example Compound V-1:
- Ester Z-33a (80%, 817 mg, 2.21 mmol) is combined with a methanolic LiOH solution (270 mg, 11.05 mmol LiOH in 35 mL MeOH). The reaction mixture is stirred overnight at 60° C. For working up the mixture is diluted with 15 mL water and extracted 1× with DCM. The aqueous phase is adjusted to an acidic pH with 2N HCl solution and extracted 5× with EE. The combined organic phases are extracted 1× with saturated NaCl solution, dried on MgSO4, filtered, evaporated down and Z-34a (HPLC-MS: tRet.=0.11 min; MS (M+H)+=282) is obtained.
- Benzoic acid Z-34a (462 mg, 1.64 mmol) is suspended in thionyl chloride (10 mL, 134 mmol). The reaction mixture is refluxed for 1 h and stirred overnight at 60° C. The excess thionyl chloride is spun off and the remainder is dried azeotropically 1× with toluene. The acid chloride Z-35a is used again directly.
- 3-amino-5-tert-butylisoxazole E-2d (58 mg, 0.40 mmol) is placed in DCM (4 mL), combined with pyridine (200 μL, 2.47 mmol) and cooled in the ice bath. Then a solution of the acid chloride Z-35a (120 mg, 0.40 mmol) in 3 mL DCM is added. The reaction mixture is stirred for 1 h at RT. For working up the mixture is diluted with water, the DCM is spun off, placed in solution with DMF and chromatographed by RP-MPLC (7% to 90% acetonitrile). The product-containing fractions of V-1 (HPLC-MS: tRet.=1.94 min; MS (M+H)+=404) are mixed with 2N HCl solution and freeze-dried.
- Analogously to the methods a) and c) to e) (synthesis route 2) or the synthesis route 1 shown, besides V-1 the following compounds V-2 to V-10 according to the invention are prepared (Table 5).
- Compound of type VI is synthesised according to synthesis route 3 shown.
- Compounds of type VII and VIII are pyrimidopyrimidines disubstituted in the 4- and 8-position (Reaction scheme F).
- Starting from 4,8-dichloro-pyrimido[5,4-d]pyrimidine P-4-a (synthesis route 4→Z-37) or the intermediate compounds Z-31, Z-32 or Z-36 (cf. their synthesis from P-4-a according to Reaction scheme E) the chlorine atoms in the 4-position are substituted by R3—H (ammonia, methylamine or water/hydroxide). The other reaction steps according to Reaction scheme F correspond to those already described.
-
- Substance Z-31b (34%, 141.0 mg, 0.109 mmol) is mixed with methylamine (2M in THF, 1 mL). The reaction mixture is stirred for 20 min at RT. For working up it is evaporated down, the residue is dissolved with DMSO, purified by preparative HPLC and example compound VII-1 (HPLC-MS: tRet.=1.85 min; MS (M+H)+=433) is obtained.
-
- 4,8-dichloropyrimidopyrimidine P-4 (2.0 g, 9.95 mmol) is placed in dioxane (40 mL) and cooled in the ice bath. The aniline A-4-a (1.514 g, 9.95 mmol) is taken up in 20 mL dioxane and added dropwise to the 4,8-dichloropyrimidopyrimidine solution. Then dipotassium hydrogen phosphate trihydrate (3 M, 6.633 mL, 19.89 mmol) is added. The reaction mixture is heated to RT and stirred overnight at 65° C. For working up the mixture is cooled and evaporated down. The residue is dissolved in DCM and washed 3× with water. The organic phase is dried on Na2SO4, filtered off, evaporated down and Z-42a (HPLC-MS: tRet.=1.81 min; MS (M+H)+=317) is obtained.
-
- Substance Z-42a (100 mg, 0.32 mmol) is mixed with methylamine (2M in THF, 2 mL). The reaction mixture is stirred for 30 min at RT. The precipitate formed is filtered off, washed with a little THF, dried in vacuo and Z-43a (HPLC-MS: tRet.=1.68 min; MS (M+H)+=312) is obtained.
-
- Nitro compound Z-43a (80 mg, 0.26 mmol) is taken up in EtOH (2 mL), mixed with ammonium chloride (7 mg, 0.13 mmol) in water (2 mL) and heated to 75° C. At this temperature iron powder (72 mg, 1.29 mmol) is added batchwise and the mixture is stirred for a further hour at 75° C. After cooling it is filtered through silica gel, washed with DCM/MeOH (9:1), the filtrate obtained is dried using the rotary evaporator and Z-44a (HPLC-MS: tRet.=1.25 min; MS (M+H)+=282) is obtained.
- Benzoic acid E-5c (40 mg, 0.21 mmol) is taken up in DCM (1 mL) and mixed with DIPEA (109 μL, 0.63 mmol) and HATU (88 mg, 0.23 mmol). After 15 min aniline Z-44a (60 mg, 0.21 mmol) is added and the mixture is stirred at RT. For working up the mixture is evaporated down, the residue is dissolved with DMSO, purified by preparative HPLC and example compound VIII-1 (HPLC-MS: tRet.=1.78 min; MS (M+H)+=453) is obtained.
- For synthesising compounds (1) according to the invention the key educts E-1, E-2, E-3, E-4, E-5, A-2 and A-4 are needed, in particular. These starting compounds may be obtained in numerous ways. A significant number of such synthesis components are commercially obtainable or may be prepared by the skilled man using routine methods. In addition, these components and their preparation are known from the prior art or may be carried out routinely analogously to methods known in the prior art or may be expanded into these. These include in particular methods published in the following publications: WO 2004/050642, WO 2005/056535, WO 2005/090333, WO 2005/115991, US 2006/100204, WO 2008/003770, WO 2005/023761, WO 2008/021388, WO 2007/075896, WO 2007/056016, WO 2008/089034, WO 2009/003999 and WO 2009/003998.
- For educts A-4 there is also the alternative possibility of obtaining them from the aromatic nitro acids A-6 by CURTIUS degradation:
- For incorporated linker units L2 which are different from —C(O)NH— and —NHC(O)—, the synthesis components required may be converted routinely. Thus, for example, instead of carboxylic acids, sulphonic acids may be used to synthesise the corresponding sulphonamides. Urea linkers are obtained by reacting isocyanates with amines or the compound of two amines via a carbonylbiselectrophil (e.g. CDI, triphosgene).
- The following Examples describe the biological activity of the compounds according to the invention, without restricting the invention to these Examples.
- Compounds of general formula (1) are characterised by their many possible applications in the therapeutic field. Particular mention should be made of those applications in which the inhibition of specific signal enzymes, particularly the inhibiting effect on the proliferation of cultivated human tumour cells but also on the proliferation of other cells such as endothelial cells, for example, are involved.
- In a dilution series 10 μL of test substance solution are placed in a multiwell plate. The dilution series is selected so that generally a range of concentrations of 2 μM to 0.119 nM or 0.017 nM is covered. If necessary the initial concentration of 2 μM is changed to 50 μM, 10 μM or 0.4 μM or 0.2857 μM and further dilution is carried out accordingly. The final concentration of DMSO is 5%. 10 μL of the B-Raf (V600E)-kinase solution are pipetted in (containing 0.5 ng B-Raf (V600E)-kinase in 20 mM Tris-HCl pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA, 0.286 mM sodium orthovanadate, 10% glycerol, 1 mg/mL bovine serum albumin, 1 mM dithiothreitol) and the mixture is incubated for 24 h at RT under with shaking. The kinase reaction is started by the addition of 20 μL ATP solution [final concentration: 250 μM ATP, 30 mM Tris-HCl pH 7.5, 0.02% Brij, 0.2 mM sodium orthovanadate, 10 mM magnesium acetate, 0.1 mM EGTA, phosphatase cocktail (Sigma, # P2850, dilution recommended by the manufacturer), 0.1 mM EGTA] and 10 μL MEK1 solution [containing 50 ng biotinylated MEK1 (prepared from purified MEK1 according to standard procedure, e.g. with EZ-Link Sulpho-NHS-LC-Biotin reagent, Pierce, #21335) and carried out for 60 min at RT with constant shaking. The reaction is stopped by the addition of 12 μL of a 100 mM EDTA solution and incubation is continued for a further 5 min. 55 μL of the reaction solution are transferred into a streptavidin-coated plate (e.g. Streptawell HighBond, Roche, #11989685001) and shaken gently for 1 h at RT, in order to bind biotinylated MEK1 to the plate. After elimination of the liquid the plate is washed five times with 200 μL of 1×PBS and 100 μL solution of primary antibody plus europium-labelled secondary antibody [Anti Phospho-MEK (Ser217/221), Cell Signaling, #9121 and Eu-Nl labeled goat-anti-rabbit antibody, Perkin Elmer, # AD0105], the primary antibody is diluted 1:2000 and the secondary antibody is diluted to 0.4-0.5 μg/mL in Delfia Assay Buffer (Perkin Elmer, #1244-111). After 1 h shaking at RT the solution is poured away and washed five times with 200 μL Delfia Wash Buffer (Perkin Elmer, #4010-0010/#1244-114). After the addition of 200 μL Enhancement Solution (Perkin Elmer, #4001-0010/#1244-105) the mixture is shaken for 10 min at RT and then measured in a Wallac Victor using the program “Delfia Time Resolved Fluorescence (Europium)”. IC50 values are obtained from these dosage-activity curves using a software program (GraphPadPrizm).
- Table 7 gives the IC50 values determined for the compounds according to the invention using the above B-RAF-kinase test.
-
TABLE 7 # IC50 [nM] I-1 26 I-2 9 I-3 9 I-4 7 I-5 5 I-6 68 I-7 3 I-8 2 I-9 3 I-10 1 I-11 1 I-12 2 I-13 4 I-14 3 I-15 1 I-16 1 I-17 1 I-18 3 I-19 57 I-20 50 I-21 22 I-22 13 I-23 14 I-24 9 I-25 3 I-26 70 I-27 83 I-28 13 I-29 15 I-30 35 I-31 58 I-32 14 I-33 12 I-34 2 I-35 2 I-36 4 I-37 4 I-38 6 I-39 5 I-40 3 I-41 5 I-42 9 I-43 4 I-52 55 I-53 21 I-54 5 I-55 <1 I-56 <1 I-57 <1 I-58 1 I-59 1 I-60 <1 I-61 <1 I-62 2 I-63 1 I-64 <1 I-65 <1 I-66 <1 I-67 3 I-68 <1 I-69 2 I-70 3 I-71 7 I-72 12 I-73 2 I-74 3 I-75 54 I-76 1 I-77 2 I-78 8 I-79 19 I-80 2 I-81 3 I-82 676 I-83 2203 I-84 11 I-85 7 I-86 4 I-87 9 I-88 10 II-1 26 II-2 41 II-3 50 II-4 81 II-5 50 II-6 96 II-7 15 II-8 2 II-9 24 II-10 25 II-11 20 II-12 7 II-13 7 II-14 4 II-15 40 II-16 45 II-17 13 II-18 9 II-19 9 III-1 2 III-2 <1 III-3 118 III-4 2 III-5 2 III-6 7 III-7 1 III-8 3 III-9 7 III-10 6 III-11 4 III-12 2 III-13 9 III-14 3 III-15 5 III-16 2 III-17 3 III-18 4 III-19 1 III-20 3 III-21 3 III-22 6 III-23 7 III-24 5 III-25 2 III-26 24 III-27 8 III-28 3 III-29 2 III-30 2 III-31 <1 III-32 1 III-33 1 III-34 2 III-35 5 III-36 3 III-37 4 III-38 5 III-39 2 III-40 2 III-41 1 III-42 64 III-43 972 III-44 >2000 III-45 283 III-46 451 III-47 95 III-48 >1000 III-49 587 III-50 5 III-51 381 III-52 2231 III-53 318 III-54 543 III-55 >150 III-56 1989 III-57 1827 III-58 88 III-59 835 III-60 230 III-61 2242 III-62 546 III-63 13 III-64 >1000 III-65 4171 III-66 1139 III-67 5 III-68 8 III-69 6 III-70 4 III-71 3 III-72 4 III-73 4 III-74 1 III-75 1 III-76 11 III-77 2 III-78 2 III-79 1 III-80 6 III-81 2 III-82 20 III-83 8 III-84 2 III-85 7 III-86 <1 III-87 3 III-88 5 III-89 4 III-90 5 III-91 1 III-92 1 III-93 1 III-94 6 III-95 2 III-96 2 III-97 4 III-98 2 III-99 5 III-100 4 III-101 1 III-102 4 III-103 2 III-104 1 III-105 3 III-106 2 III-107 1 III-108 <1 III-109 2 III-110 1 III-111 <1 III-112 2 III-113 2 III-114 2 III-115 2 III-116 <1 III-117 2 III-118 2 III-119 3 III-120 3 III-121 2 III-122 2 III-123 <1 III-124 3 III-125 4 III-126 <1 III-127 3 III-128 3 III-129 2 III-130 3 III-131 2 III-132 <1 III-133 <1 III-134 2 III-135 4 III-136 3 III-137 3 III-138 <1 III-139 3 III-140 5 III-141 2 III-142 3 III-143 2 III-144 <1 III-145 2 III-146 <1 III-147 1 III-148 1 III-149 <1 III-150 2 III-151 1 III-152 <1 III-153 <1 III-154 4 III-155 2 III-156 <1 III-157 3 III-158 7 III-159 5 III-160 3 III-161 6 III-162 <1 III-163 9 III-164 2 III-165 <1 III-166 4 III-167 5 III-168 <1 III-169 1 III-170 <1 III-171 3 III-172 2 III-173 1 III-174 2 III-175 <1 III-176 4 III-177 4 III-178 2 III-179 >7000 III-180 3 III-181 17 III-182 245 III-183 >15000 III-184 2880 III-185 >15000 III-186 26 III-187 >2000 III-188 104 III-189 >15000 III-190 1535 III-191 >15000 III-192 2 III-193 >15000 III-194 >2000 III-195 59 III-196 16 III-197 >15000 III-198 11 III-199 23 III-200 971 III-201 >10000 III-202 >2000 III-203 >10000 III-204 4 III-205 >2000 III-206 2 III-207 11 III-208 >2000 III-209 162 III-210 >2000 III-211 4 III-212 >15000 III-213 3 III-214 56 III-215 >10000 III-216 3 III-217 2 III-218 293 III-219 8 III-220 5 III-221 171 III-222 <1 III-223 15 III-224 <1 III-225 2 III-226 101 III-227 41 III-228 5 III-229 1 III-230 6 III-231 29 III-232 4 III-233 571 III-234 15 III-235 2 III-236 1124 III-237 2 III-238 87 III-239 6 III-240 4 III-241 48 III-242 19 III-243 <1 III-244 <1 III-245 460 III-246 29 III-247 1 III-248 2 III-249 10 III-250 40 III-251 19 III-252 8 III-253 269 III-254 2000 III-255 23 III-256 15000 III-257 61 III-258 15000 III-259 505 III-260 2000 III-261 <1 III-262 9 III-263 15 III-264 2600 III-265 4 III-266 1 III-267 836 III-268 120 III-269 33 III-270 20 III-271 10 III-272 2 III-273 31 III-274 3 III-275 2 III-276 6 III-277 23 III-278 88 III-279 6 III-280 10000 III-281 5 III-282 1400 III-283 3 III-284 3 III-285 274 III-286 3 III-287 1 III-288 2 III-289 13 III-290 1 III-291 21 III-292 36 III-293 7 III-294 1 III-295 17 III-296 198 III-297 1 III-298 1 III-299 5 III-300 4 III-301 <1 III-302 115 III-303 7 III-304 <1 III-305 2 III-306 4 III-307 114 III-308 47 III-309 4 III-310 50 III-311 2 III-312 27 III-313 200 III-314 9 III-315 <1 III-316 3 III-317 14 III-318 2 III-319 1 III-320 2 III-321 <1 III-322 1 III-323 11 III-324 55 III-325 1400 III-326 292 III-327 56 III-328 442 III-329 17 III-330 6 III-331 10 III-332 4 III-333 56 III-334 10 III-335 8 III-336 140 III-337 2 III-338 41 III-339 1 III-340 4 III-341 <1 III-342 2121 III-343 2 III-344 7 III-345 1 III-346 7000 III-347 1 III-348 <1 III-349 <1 III-350 <1 III-351 <1 III-353 <1 III-354 20 III-355 <1 III-356 <1 III-357 <1 III-358 1 III-359 2 III-360 3 III-361 2 III-362 3 III-363 <1 III-364 <1 III-365 1 III-366 6 III-367 2 III-368 14 III-369 2 III-370 1 III-372 5 III-373 8 III-374 2000 III-375 2000 III-376 7 III-377 4 III-378 8 III-379 6 III-380 1400 III-381 3 III-382 <1 III-383 4 III-384 2 III-385 2 III-386 1 III-387 2 III-388 <1 III-389 <1 III-390 <1 III-391 1 III-392 3 III-393 1 III-394 1 III-395 4 III-396 3 III-397 4 III-398 1 III-399 2 III-400 4 III-401 3 III-402 2 III-403 3 III-404 6 III-405 5 III-406 3 III-407 10 III-408 25 III-409 9 III-410 1 III-411 3 III-412 5 III-413 <1 III-414 7 III-415 3 III-416 1 III-417 <1 III-418 2 III-419 1 III-420 1 III-421 12 III-422 5 III-423 <1 III-424 6 III-425 7 III-426 <1 III-427 2 III-428 <1 III-429 2 III-430 7 III-431 3 III-432 6 III-433 7 III-435 1 III-436 2 III-437 2 III-438 6 III-439 4 III-440 272 III-441 2 III-442 1 III-443 1 III-444 4 III-445 2 III-446 6 III-447 13 III-448 8 III-449 3 III-450 3 III-454 4 III-455 8 III-456 3 III-457 4 III-458 1 III-459 2 III-460 4 III-461 2 III-462 1 III-463 2 III-465 2 III-467 2 III-468 <1 III-469 <1 III-470 2 III-471 4 III-472 2 III-473 1 III-474 1 III-476 17 III-480 4 III-481 1 III-482 4 III-483 1 III-484 3 III-485 3 III-486 4 III-487 13 III-488 6 III-489 1 III-490 2 III-491 2 III-492 2 III-493 5 III-494 4 III-495 2 III-496 2 III-497 2 III-499 3 III-500 <1 III-501 25 III-502 8 III-503 1 III-504 2 III-505 49 III-506 4 III-507 1 III-508 3 III-509 5 III-510 <1 III-511 4 III-512 2 III-513 1 III-514 1 III-515 <1 III-516 <1 III-517 3 III-518 2 III-519 <1 III-520 2 III-521 2 III-522 3 III-523 1 III-524 3 III-525 3 III-526 4 III-527 <1 III-528 2 III-529 3 III-530 582 III-531 13 III-532 2 III-533 6 III-534 106 III-535 4 III-536 1 III-537 12 III-538 10 III-539 2 III-540 5 III-541 15 III-542 12 III-543 3 III-544 1 III-545 2 III-546 4 III-547 <1 III-548 3 III-549 8 III-550 4 III-551 1 III-552 17 III-553 2 III-554 3 III-555 18 III-556 7 III-557 4 III-558 23 III-559 14 III-560 7 III-561 9 III-562 1 III-563 2 III-564 1 III-565 11 III-567 2 III-568 1 III-569 2 III-570 <1 III-571 2 III-572 1 III-575 3 III-577 2 III-580 28 III-581 33 III-582 74 III-583 32 III-584 18 III-585 27 III-586 193 III-587 65 III-591 1 III-592 <1 III-593 1 III-594 1 III-595 1 III-596 2 III-597 5 III-598 <1 III-599 1 III-600 3 III-601 6 III-602 9 III-603 1 III-604 3 III-605 6 III-606 3 III-607 1 III-608 7 IV-1 13 IV-2 <1 IV-3 12 IV-4 44 IV-5 129 IV-7 1 IV-10 221 IV-12 1 IV-13 3 IV-15 3 IV-18 9 IV-22 2 IV-23 4 IV-24 72 IV-26 2 IV-27 1 IV-28 1 IV-29 1 IV-30 <1 IV-31 5 IV-32 1 IV-33 2 IV-34 2 IV-35 2 IV-36 4 IV-37 1 IV-38 2 IV-39 4 IV-40 2 IV-42 13 IV-46 3 IV-50 59 IV-53 10000 IV-54 10000 IV-55 10000 IV-56 10000 IV-57 10000 IV-58 49 IV-59 2000 IV-60 2000 IV-61 10000 IV-62 2000 IV-63 595 IV-64 521 IV-65 2000 IV-66 10000 IV-67 2 IV-68 3 V-1 2 V-8 4 V-9 5 V-10 14 VII-1 1 VIII-1 <1 VIII-2 30 VIII-3 13 - For measuring the proliferation of cultivated human tumour cells, cells of the melanoma cell line SK-MEL-28 [American Type Culture Collection (ATCC)] are cultivated in MEM medium, supplemented with 10% foetal calf serum, 2% sodium bicarbonate, 1 mM sodium pyruvate, 1% non-essential amino acids (e.g. from Cambrex, # BE13-114E) and 2 mM glutamine. SK-MEL28 cells are placed in 96-well flat bottomed dishes in a density of 2500 cells per well in supplemented MEM medium (see above) and incubated overnight in an incubator (at 37° C. and 5% CO2). The active substances are added to the cells in different concentrations, so that a concentration range of 50 μM to 3.2 nM is covered. If necessary the initial concentration of 50 μM is changed to 10 μM or 2 μM and further dilution is carried out accordingly (to 0.6 nM or 0.12 nM). After an incubation period of a further 72 h 20 μL AlamarBlue reagent (Serotec Ltd., # BUF012B) are added to each well and the cells are incubated for a further 3-6 h. The colour change of the AlamarBlue reagent is determined in a fluorescence spectrophotometer (e.g. Gemini, Molecular Devices). EC50 values are calculated using a software program (GraphPadPrizm).
- For measuring the proliferation of cultivated human tumour cells, cells of the melanoma cell line A375 [American Type Culture Collection (ATCC)] are cultivated in DMEM medium, supplemented with 10% foetal calf serum and 2% sodium bicarbonate. Test substances are tested on A375 cells according to the procedure described for SK-MEL28 cells (see above), but seeding them at 5000 cells per well.
- Most of the example compounds of types I to VIII (Tables 1 to 6) show good to very good activity in the cellular A375 and SK-MEL-28 proliferation test, i.e. an EC50 value of less than 5 μM, generally less than 1 μM.
- The active substances are characterised in that they have a significantly lower antiproliferative effect on cell lines that do not have a B-RAF mutation, i.e. the EC50 value is generally higher, by a factor of 10, than the EC50 value of B-RAF mutated cell lines.
- The cellular selectivity of the active substances is demonstrated by the fact that the EC50 value of the phospho-ERK reduction correlates with the EC50 value of the antiproliferative activity in B-RAF mutated cell lines.
- In order to measure the reduction in the phospho-ERK signal of cultivated human tumour cells, cells of the melanoma cell line SK-MEL-28 [American Type Culture Collection (ATCC)] are cultivated in MEM medium, supplemented with 10% foetal calf serum, 2% sodium bicarbonate, 1 mM sodium pyruvate, 1% non-essential amino acids (e.g. from Cambrex, # BE13-114E) and 2 mM glutamine. SK-MEL28 cells are placed in 96-well flat bottomed dishes at a density of 7500 cells per well in supplemented MEM medium (see above) and incubated overnight in an incubator (at 37° C. and 5% CO2). The active substances are added to the cells in different concentrations, so that a concentration range of 10 μM to 2.4 nM is covered. If necessary the initial concentration of 10 μM is changed to 50 μM or 2.5 μM and further dilution is carried out accordingly (to 12.2 nM or 0.6 nM). After an incubation period of a further 2 h the cells are fixed with 4% formaldehyde and rendered permeable with 0.1% Triton X-100 in PBS. Non-specific antibody binding is reduced by incubation with 5% skimmed milk powder dissolved in TBS-T. Phosphorylated ERK is detected with a mouse monoclonal anti-diphosphorylated ERK1/2 antibody (from Sigma, #M8159). After washing steps with 0.1% Tween 20 in PBS the bound first antibody is detected by the second antibody (peroxidase coupled polyclonal rabbit anti mouse IgG from DAKO #P0161). After further washing steps, the substrate (TMB Peroxidase Substrate Solution from Bender MedSystems #BMS406) is added. The colour reaction is stopped after a few minutes with 1 M phosphoric acid. The colour is measured with a Spectra max Plus reader from Molecular Devices at 450 nm. EC50 values are calculated using a software program (GraphPadPrizm).
- The substances of the present invention are B-RAF-kinase inhibitors. As can be demonstrated by DNA staining followed by FACS or Cellomics Array Scan analysis, the inhibition of proliferation achieved by means of the compounds according to the invention is brought about above all by preventing entry into the DNA synthesis phase. The treated cells arrest in the G1 phase of the cell cycle.
- Accordingly, the compounds according to the invention are also tested on other tumour cells. For example these compounds are effective on the colon carcinoma line, e.g. Colo205, and may be used in this and other indications. This demonstrates the usefulness of the compounds according to the invention for the treatment of different types of tumours.
- On the basis of their biological properties the compounds of general formula (1) according to the invention, their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and the salts of all the above-mentioned forms are suitable for treating diseases characterised by excessive or abnormal cell proliferation.
- Such diseases include for example: viral infections (e.g. HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukaemias, lymphomas and solid tumours (e.g. carcinomas and sarcomas), skin diseases (e.g. psoriasis); diseases based on hyperplasia which are characterised by an increase in the number of cells (e.g. fibroblasts, hepatocytes, bones and bone marrow cells, cartilage or smooth muscle cells or epithelial cells (e.g. endometrial hyperplasia)); bone diseases and cardiovascular diseases (e.g. restenosis and hypertrophy). They are also suitable for protecting proliferating cells (e.g. hair, intestinal, blood and progenitor cells) from DNA damage caused by radiation, UV treatment and/or cytostatic treatment.
- For example, the following cancers may be treated with compounds according to the invention, without being restricted thereto: brain tumours such as for example acoustic neurinoma, astrocytomas such as pilocytic astrocytomas, fibrillary astrocytoma, protoplasmic astrocytoma, gemistocytary astrocytoma, anaplastic astrocytoma and glioblastoma, brain lymphomas, brain metastases, hypophyseal tumour such as prolactinoma, HGH (human growth hormone) producing tumour and ACTH producing tumour (adrenocorticotropic hormone), craniopharyngiomas, medulloblastomas, meningeomas and oligodendrogliomas; nerve tumours (neoplasms) such as for example tumours of the vegetative nervous system such as neuroblastoma sympathicum, ganglioneuroma, paraganglioma (pheochromocytoma, chromaffinoma) and glomus-caroticum tumour, tumours on the peripheral nervous system such as amputation neuroma, neurofibroma, neurinoma (neurilemmoma, Schwannoma) and malignant Schwannoma, as well as tumours of the central nervous system such as brain and bone marrow tumours; intestinal cancer such as for example carcinoma of the rectum, colon, anus, small intestine and duodenum; eyelid tumours such as basalioma or basal cell carcinoma; pancreatic cancer or carcinoma of the pancreas; bladder cancer or carcinoma of the bladder; lung cancer (bronchial carcinoma) such as for example small-cell bronchial carcinomas (oat cell carcinomas) and non-small cell bronchial carcinomas such as plate epithelial carcinomas, adenocarcinomas and large-cell bronchial carcinomas; breast cancer such as for example mammary carcinoma such as infiltrating ductal carcinoma, colloid carcinoma, lobular invasive carcinoma, tubular carcinoma, adenocystic carcinoma and papillary carcinoma; non-Hodgkin's lymphomas (NHL) such as for example Burkitt's lymphoma, low-malignancy non-Hodgkin's lymphomas (NHL) and mucosis fungoides; uterine cancer or endometrial carcinoma or corpus carcinoma; CUP syndrome (Cancer of Unknown Primary); ovarian cancer or ovarian carcinoma such as mucinous, endometrial or serous cancer; gall bladder cancer; bile duct cancer such as for example Klatskin tumour; testicular cancer such as for example seminomas and non-seminomas; lymphoma (lymphosarcoma) such as for example malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas (NHL) such as chronic lymphatic leukaemia, leukaemic reticuloendotheliosis, immunocytoma, plasmocytoma (multiple myeloma), immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungoides, large-cell anaplastic lymphoblastoma and lymphoblastoma; laryngeal cancer such as for example tumours of the vocal cords, supraglottal, glottal and subglottal laryngeal tumours; bone cancer such as for example osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant cell tumour, chondrosarcoma, osteosarcoma, Ewing's sarcoma, reticulo-sarcoma, plasmocytoma, fibrous dysplasia, juvenile bone cysts and aneurysmatic bone cysts; head and neck tumours such as for example tumours of the lips, tongue, floor of the mouth, oral cavity, gums, palate, salivary glands, throat, nasal cavity, paranasal sinuses, larynx and middle ear; liver cancer such as for example liver cell carcinoma or hepatocellular carcinoma (HCC); leukaemias, such as for example acute leukaemias such as acute lymphatic/lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML); chronic leukaemias such as chronic lymphatic leukaemia (CLL), chronic myeloid leukaemia (CML); stomach cancer or gastric carcinoma such as for example papillary, tubular and mucinous adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, small-cell carcinoma and undifferentiated carcinoma; melanomas such as for example superficially spreading, nodular, lentigo-maligna and acral-lentiginous melanoma; renal cancer such as for example kidney cell carcinoma or hypernephroma or Grawitz's tumour; oesophageal cancer or carcinoma of the oesophagus; penile cancer; prostate cancer; throat cancer or carcinomas of the pharynx such as for example nasopharynx carcinomas, oropharynx carcinomas and hypopharynx carcinomas; retinoblastoma such as for example vaginal cancer or vaginal carcinoma; plate epithelial carcinomas, adenocarcinomas, in situ carcinomas, malignant melanomas and sarcomas; thyroid carcinomas such as for example papillary, follicular and medullary thyroid carcinoma, as well as anaplastic carcinomas; spinalioma, epidormoid carcinoma and plate epithelial carcinoma of the skin; thymomas, cancer of the urethra and cancer of the vulva.
- The new compounds may be used for the prevention, short-term or long-term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy or other “state-of-the-art” compounds, such as e.g. cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies.
- The compounds of general formula (1) may be used on their own or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances.
- Chemotherapeutic agents which may be administered in combination with the compounds according to the invention, include, without being restricted thereto, hormones, hormone analogues and antihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g. goserelin acetate, luprolide), inhibitors of growth factors (growth factors such as for example “platelet derived growth factor” and “hepatocyte growth factor”, inhibitors are for example “growth factor” antibodies, “growth factor receptor” antibodies and tyrosinekinase inhibitors, such as for example cetuximab, gefitinib, imatinib, lapatinib and trastuzumab); antimetabolites (e.g. antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil, capecitabin and gemcitabin, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine); antitumour antibiotics (e.g. anthracyclins such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g. Cisplatin, oxaliplatin, carboplatin); alkylation agents (e.g. Estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as for example carmustin and lomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such as for example vinblastine, vindesin, vinorelbin and vincristine; and taxanes such as paclitaxel, docetaxel); topoisomerase inhibitors (e.g. epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantron) and various chemotherapeutic agents such as amifostin, anagrelid, clodronat, filgrastin, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer.
- Suitable preparations include for example tablets, capsules, suppositories, solutions—particularly solutions for injection (s.c., i.v., i.m.) and infusion—elixirs, emulsions or dispersible powders. The content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below. The doses specified may, if necessary, be given several times a day.
- Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.
- Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
- Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
- Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.
- Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules. Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
- Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).
- The preparations are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route. For oral administration the tablets may, of course contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.
- For parenteral use, solutions of the active substances with suitable liquid carriers may be used.
- The dosage for intravenous use is from 1-1000 mg per hour, preferably between 5 and 500 mg per hour.
- However, it may sometimes be necessary to depart from the amounts specified, depending on the body weight, the route of administration, the individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered. Thus, in some cases it may be sufficient to use less than the minimum dose given above, whereas in other cases the upper limit may have to be exceeded. When administering large amounts it may be advisable to divide them up into a number of smaller doses spread over the day.
- The formulation examples which follow illustrate the present invention without restricting its scope:
-
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A) Tablets per tablet active substance according to formula (1) 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 mg - The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.
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B) Tablets per tablet active substance according to formula (1) 80 mg lactose 55 mg corn starch 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg - The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.
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C) Ampoule solution active substance according to formula (1) 50 mg sodium chloride 50 mg water for inj. 5 mL - The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
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US20110183952A1 (en) * | 2007-07-02 | 2011-07-28 | Boehringer Ingelheim International Gmbh | New chemical compounds |
US8889665B2 (en) | 2007-07-02 | 2014-11-18 | Boehringer Ingelheim International Gmbh | Chemical compounds |
US8653087B2 (en) | 2008-09-08 | 2014-02-18 | Boehringer Ingelheim International Gmbh | Pyrido [5, 4-D] pyrimidines as cell proliferation inhibitors |
US8778929B2 (en) | 2008-09-29 | 2014-07-15 | Boehringer Ingelheim International Gmbh | Substituted heteroaryl inhibitors of B-RAF |
US8569316B2 (en) | 2009-02-17 | 2013-10-29 | Boehringer Ingelheim International Gmbh | Pyrimido [5,4-D] pyrimidine derivatives for the inhibition of tyrosine kinases |
US8865703B2 (en) | 2010-03-26 | 2014-10-21 | Boehringer Ingelheim International Gmbh | Pyridyltriazoles |
US9290507B2 (en) | 2010-03-26 | 2016-03-22 | Boehringer Ingelheim International Gmbh | B-RAF kinase inhibitors |
US8710055B2 (en) | 2010-12-21 | 2014-04-29 | Boehringer Ingelheim International Gmbh | Triazolylphenyl sulfonamides as serine/threonine kinase inhibitors |
Also Published As
Publication number | Publication date |
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RU2011113402A (en) | 2012-10-20 |
MX2011002431A (en) | 2011-04-05 |
JP2012502010A (en) | 2012-01-26 |
ZA201101090B (en) | 2012-10-31 |
US8653087B2 (en) | 2014-02-18 |
WO2010026262A1 (en) | 2010-03-11 |
EP2350083B1 (en) | 2017-05-17 |
CA2736306A1 (en) | 2010-03-11 |
CN102203098A (en) | 2011-09-28 |
IL211136A0 (en) | 2011-04-28 |
AR073501A1 (en) | 2010-11-10 |
NZ591493A (en) | 2012-07-27 |
TW201014860A (en) | 2010-04-16 |
KR20110063528A (en) | 2011-06-10 |
CL2011000489A1 (en) | 2011-07-15 |
JP5576379B2 (en) | 2014-08-20 |
AU2009289196A1 (en) | 2010-03-11 |
EP2350083A1 (en) | 2011-08-03 |
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